Adsorption Of Lipoproteins Research Articles

Impact of selective LDL apheresis on serum chemerin levels in patients with hypercholesterolemia.

BackgroundSelective low-density lipoprotein (LDL) apheresis is commonly used to treat patients with familial hypercholesterolemia (FH). Chemerin is an adipokine with putative roles in the regulation of lipid metabolism.MethodsIn our pilot study, we measured serum chemerin levels by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments using the technique of direct adsorption of lipoproteins (DALI).ResultsThe first treatment sessions decreased serum chemerin levels by an average of 27.26 %. While following one patient, 12 months of regular LDL apheresis resulted in a permanent reduction in his serum chemerin level. Changes in the lipoprotein subfractions measured by gel electrophoresis (Lipoprint) correlated with the reduction of chemerin levels. Furthermore, we eluted and then measured chemerin bound to the DALI column.ConclusionWe conclude that LDL apheresis decreases the circulating level of chemerin by binding the protein to the column and thus improves lipoprotein subfraction pattern.

Successful Direct Adsorption of Lipoproteins (DALI) Apheresis During Pregnancy in an Omani Woman with Homozygous Familial Hypercholesterolemia.

We report our experience with Direct Adsorption of Lipoproteins (DALI) apheresis in an Omani pregnant woman affected by homozygous familial hypercholesterolemia. To the best of our knowledge this is the first successful pregnancy treated with DALI apheresis. The patient had a history of coronary artery disease, supra-aortic valvular stenosis and severe carotid artery disease with right carotid artery stenting. She was on a regular biweekly DALI apheresis since 2008. In May 2013, she became pregnant and rosuvastatin and ezetimibe were stopped while she continued on DALI apheresis biweekly. This treatment during pregnancy was successful with no major complications. The average low-density lipoprotein cholesterol reduction during therapy was 50%. She spontaneously delivered a healthy male infant (2,400 g) at 37 weeks. We showed that DALI apheresis therapy was safe during pregnancy with a good outcome for both mother and neonate.

LDL apheresis in the treatment of familial hypercholesterolemia: Experience of Hospital Santo António, Porto

IntroductionHigh plasma levels of low-density lipoprotein (LDL) cholesterol are a risk factor for the development of premature atherosclerosis. Direct adsorption of lipoproteins (DALI) is an apheresis technique by which LDL cholesterol is selectively removed from whole blood. ObjectiveThe present study describes our experience with DALI LDL apheresis in severely hypercholesterolemic patients. MethodsThree hypercholesterolemic patients suffering from atherosclerotic complications were treated fortnightly by DALI apheresis, in a total of 308 sessions between December 2008 and January 2013. All patients were on the highest tolerated dose of statins and other lipid-lowering drugs. ResultsThe sessions were essentially uneventful, adverse events being recorded in only 3.6% of them. A mean 63.3% acute reduction in LDL cholesterol was obtained. ConclusionsDALI apheresis proved to be a simple, safe and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid-lowering therapy.

LDL‐aférese no tratamento de hipercolesterolemia familiar: experiência do Hospital Santo António

IntroductionHigh plasma levels of low‐density lipoprotein (LDL) cholesterol are a risk factor for the development of premature atherosclerosis.Direct adsorption of lipoproteins (DALI) is an apheresis technique by which LDL cholesterol is selectively removed from whole blood. ObjectiveThe present study describes our experience with DALI LDL apheresis in severely hypercholesterolemic patients. MethodsThree hypercholesterolemic patients suffering from atherosclerotic complications were treated fortnightly by DALI apheresis, in a total of 308 sessions between December 2008 and January 2013. All patients were on the highest tolerated dose of statins and other lipid‐lowering drugs. ResultsThe sessions were essentially uneventful, adverse events being recorded in only 3.6% of them. A mean 63.3% acute reduction in LDL cholesterol was obtained. ConclusionDALI apheresis proved to be a simple, safe and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid‐lowering therapy.

Polydopamine-assisted deposition of heparin for selective adsorption of low-density lipoprotein

Low-density lipoprotein (LDL) is the main carrier of blood cholesterol, with elevated levels of LDL increasing the risk of atherosclerosis.

Surface glycosylation of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) membrane for selective adsorption of low-density lipoprotein

A novel method of constructing a glycosylated surface on poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] membrane surface for the selective adsorption of low-density lipoprotein (LDL) was developed, which involved the photoinduced graft polymerization of acrylic acid followed by the chemical binding of carboxyl groups with glucosamine in the presence of 1-ethyl-3-(dimethyl-aminopropyl) carbodiimide hydrochloride and N-hydroxy-succinimide. The chemical structures of the fabricated membranes were characterized by attenuated total reflectance Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Zeta potential and water contact angle measurements were performed to investigate the surface charge and wettability of the membranes, respectively. An enzyme linked immunosorbent assay was used to measure the LDL adsorption on the plain and modified membrane surfaces. It was found that the surface glycosylation of P(3HB-co-4HB) membrane greatly enhanced the affinity interactions with LDL and the absorbed LDL could be easily desorbed with eluents, indicating a specific and reversible binding of LDL to the surface. Furthermore, the hemocompatibility of glycosylated membrane was improved as examined by platelet adhesion. The results suggest that the glycosylated P(3HB-co-4HB) membrane is promising for application in LDL apheresis therapy.

Effects of lipoprotein apheresis (la) on serum pcsk9 levels

Objectives: PCSK9 plays an important role in the regulation of LDLcholesterol concentrations via its influence on catabolism of the LDL receptors. It is known that PCSK9 levels are higher in patients with familial hypercholesterolemia than in normolipidemic controls. We wanted to estimate PCSK9 levels in patients currently undergoing apheresis or eligible to be treated by LA and look into the acute effects of LA on PCSK9 concentrations. Methods: We measured total serum PCSK9 levels (using an ELISA-method) in 2 cohorts: Cohort I consisted of patients actively undergoing lipoprotein apheresis as part of their routine care (n 40; 21 males, 19 females; age 55.6 years (range 32-73 years)). Blood was drawn before and immediately after 3 apheresis sessions (paying attention to standardized conditions). The following LA methods were used: Dextran Sulfate cellulose Adsorption (DSA), Heparin Extracorporeal LDL Precipitation (HELP) system, Double filtration plasmapheresis (DFPP), Direct Adsorption of Lipoproteins (DALI), and “other” systems. Cohort II consisted of patients who were eligible for lipoprotein apheresis but not undergoing the procedure (n 10; 3 males, 7 females; age 61.1 years (range 50-78 years)). Results: Mean PCSK9 pre-apheresis levels were 253.70 ng/mL in Cohort I, were decreased by approximately 50 % by LA, but returned to the preapheresis levels on the second dayafter the apheresis. It appeared that when compared with the DSA method HELP showed a more pronounced decline in PCSK9 concentrations, whereas DALI was associated with a less pronounced reduction than DSA. In Cohort II mean PCSK9 levels were 287.00 ng/mL. Conclusion: LA treatment reduced PCSK9 by approximately 50%, with the extent of reduction being dependent upon the type of apheresis method used. The PCSK9 concentrations were slightly higher in subjects eligible for, but not undergoing, apheresis compared to patients that were actively undergoing apheresis.

Immobilization of sodium alginate sulfates on polysulfone ultrafiltration membranes for selective adsorption of low-density lipoprotein

A novel method for the immobilization of sodium alginate sulfates (SAS) on polysulfone (PSu) ultrafiltration membranes to achieve selective adsorption of low-density lipoprotein (LDL) was developed, which involved the photoinduced graft polymerization of acrylamide on the membrane and the Hofmann rearrangement reaction of grafted acrylamide followed by chemical binding of SAS with glutaraldehyde. The surface modification processes were confirmed by attenuated total reflectance Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy characterization. Zeta potential and water contact angle measurements were performed to investigate the surface charge and wettability of the membranes. An enzyme-linked immunosorbent assay was used to measure the binding of LDL on plain and modified PSu membranes. It was found that the PSu membrane immobilized with sodium alginate sulfates (PSu-SAS) greatly enhanced the selective adsorption of LDL from protein solutions and the absorbed LDL could be easily eluted with sodium chloride solution, indicating a specific and reversible binding of LDL to SAS, mainly driven by electrostatic forces. Furthermore, the PSu-SAS membrane showed good blood compatibility as examined by platelet adhesion. The results suggest that the PSu-SAS membranes are promising for application in simultaneous hemodialysis and LDL apheresis therapy.

Bioinspired Multiple-Interaction Model Revealed in Adsorption of Low-Density Lipoprotein to Surface Containing Saccharide and Alkanesulfonate

A new "multiple-interaction model" for low-density lipoprotein (LDL) adsorption to a specific surface containing saccharide and alkanesulfonate ligands is proposed. The model suggests that there are interactions of the saccharide component beyond electrostatic interactions of the alkanesulfonate component that both influence the LDL adsorption process. This concept of multiple interactions between saccharide and LDL was inspired by the similarity in structures of LDL receptors (LDLR), heparin, and heparans used in LDL-apheresis. The model was confirmed by SPR analysis by the adsorption maxima on SAM surfaces with different compositions of saccharide and alkanesulfonate and additionally by CD detection of the conformation of LDL when in contact with saccharide.

Cooperative Adsorption of Lipoprotein Phospholipids, Triglycerides, and Cholesteryl Esters Are a Key Factor in Nonspecific Adsorption from Blood Plasma to Antifouling Polymer Surfaces

Nonspecific protein adsorption is a central challenge for the use of polymeric materials in biological media. While the quantity of adsorbed protein can be lowered, very few surfaces are protein resistant when exposed to undiluted serum or plasma. The underlying principles of this fouling and the adsorbing proteins remain to be identified. Here, we investigated adsorption from undiluted human blood plasma to three different polymer brushes. Our study showed that the polymer structure does not influence which proteins adsorb. Further, we identified 98 plasma proteins that still foul current "protein-resistant" polymer brushes. Detailed studies into the major adsorbing protein revealed the central role that lipoproteins and low density lipoprotein in particular play in fouling of plasma to polymeric biomaterials. However, although apolipoprotein B100 is found as a major fouling protein in our mass spectrometry screening, studies on individual components of lipoproteins show that it is not apoB100 but a mixture of phospholipids, triglycerides, and cholesteryl esters that plays a major role in lipoprotein adsorption.

Human Serum Lipoproteins Influence Protein Deposition Patterns on Nanoparticle Surfaces

We report the concentration-dependent adsorption of serum lipoproteins onto silica nanoparticles, wherein elevated lipid levels deter complement activation. Two clinically relevant serum lipid levels - corresponding to low and borderline high levels in normal, healthy adults - were used to examine the influence of lipoprotein concentration on nanoparticle complement activation. Human serum albumin was used to study protein adsorption in the presence of lipoproteins. Preferential adsorption of high affinity lipoproteins led to greater lipid fractions in the protein corona, shielding particles from complement activation. These findings have significant implications for the design of intravenously administered carriers with biocompatible surface chemistries.

Successful treatment of monomorphic primary central nervous system post‐transplantation lymphoproliferative disorder 5 years after kidney transplantation

A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole-brain radiation and discontinuation of immunosuppression therapy.

Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia

We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(∼10 mg/dl; range 10-11 mg/dl), intermediate (∼50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins.

Changes in Lipids and Lipoproteins after Selective LDL Apheresis (7-Year Experience).

Background. The aim of the study was to investigate the changes in plasma lipids and lipoproteins and the cardiovascular events after selective LDL apheresis. Methods and Results. Two pediatric patients with familial hypercholesterolemia aged 11 and 13 years and 19 dyslipidemic adults aged 41 ± 14 years underwent direct adsorption of lipoproteins (DALI) sessions. The mean follow-up period was 47 ± 23 months. The total cholesterol (TC) values before and after treatment were 8.2 ± 2.2 and 3.1 ± 1.6 mmol/l (318 ± 86 and 122 ± 62 mg/dL), respectively. The interval mean of TC was 6.9 ± 1.9 mmol/l (268 ± 75 mg/dL). The LDL cholesterol concentrations before and after treatment were 6.6 ± 2.1 and 1.7 ± 1.1 mmol/l, (256 ± 82 mg/dL and 65 ± 41 mg/dL), respectively. The percentage of acute LDL cholesterol reduction was 75 ± 11%. Cardiovascular events were observed in seven patients. The average annual event rate was 5.51%. Conclusion. LDL apheresis is a very important therapeutic tool in managing patients at high risk for premature CAD or with aggressive CAD, despite adequate medical treatment.

Polyacrylate adsorbents for the selective adsorption of cholesterol-rich lipoproteins from plasma or blood.

Polyacrylate (PAA) adsorbents selectively bind low density lipoproteins (LDL) from human plasma and blood, whereas very low density lipoproteins (VLDL) are only minimally adsorbed. The adsorption of cholesterol-rich lipoproteins to PAA adsorbents is related to the molecular weight (mw) of the polyanion ligand. Ca++ and Mg++ inhibit the binding of LDL to PAA adsorbents. The chemical composition of the organic hardgels of the adsorbents does not have an influence on adsorption. The selective adsorption of LDL to PAA adsorbents can be explained to result from their low negative surface charge density and the specific colloid-chemical properties of the surface-bound PAA, which do not prevent LDL from binding to charge-like domains of the ligand. By contrast, VLDL and high density lipoproteins (HDL) are repelled from the adsorbents due to their higher negative surface charge density.

Adsorption of low-density lipoprotein, its oxidation, and subsequent binding of specific recombinant antibodies: An in situ ellipsometric study

Background Low-density lipoprotein (LDL) particles accumulate in the arterial wall and become oxidized during atherogenesis, leading to the formation of atherosclerotic plaques. The major protein of the LDL particle, apolipoprotein B-100 (apoB-100), becomes fragmented during oxidation and a target for the immune system. Methods In this study we used in situ ellipsometry to monitor the adsorption of LDL to solid silica surfaces and the effects of oxidation on the structure of the adsorbed LDL layer. We additionally investigated the binding kinetics of two recombinant human antibodies with different specificities recognizing epitopes of apoB-100 in surface-bound native and CuCl 2-oxidized LDL (oxLDL). The latter process was studied by adsorbing LDL and then adding the antibody and CuCl 2 while continuously monitoring adsorbed amount and the thickness of the film. The molar ratios between the antibodies and surface-bound LDL and oxLDL were calculated from these data. Results Our results indicate that oxidation of surface-bound LDL induces swelling of the layer, accompanied by a slight desorption. We further found that both antibodies were able to recognize LDL and oxLDL in its adsorbed orientation. Quantitative information was obtained on the number of available binding sites on surface-bound LDL and oxLDL for these two antibodies. General significance Using ellipsometry for real-time monitoring of adsorption, in situ oxidation of LDL and binding of specific recombinant antibodies to surface-bound LDL, will open up possibilities to map different conformations and orientations of LDL in the adsorbed state.

Successful treatment of recurrent focal segmental glomerulosclerosis combined with calcineurin inhibitor nephrotoxicity four yr after kidney transplantation

A 31-yr-old Japanese man with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent living related kidney transplantation at the age of 26 yr. The allograft functioned well immediately after surgery, and we did not observe histological findings of rejection and recurrent FSGS in protocol biopsies at two months and one yr after transplantation. Four years after transplantation, the urine protein excretion reached 11 g/d, and the serum creatinine increased over 2.5 mg/dL. We diagnosed nephrotic syndrome due to recurrent FSGS with graft dysfunction and confirmed FSGS lesions with severe endothelial injury with an allograft biopsy, associated with calcineurin inhibitor (CNI) nephrotoxicity. Thereafter, we performed plasmapheresis and steroid therapy with subsequent low-density lipoprotein adsorption, combined with the reduction of tacrolimus. The nephrotic syndrome improved dramatically with the multiple therapeutic approaches. Primary FSGS recurs frequently in patients immediately after kidney transplantation. Post-transplant FSGS has various causes, such as recurrent primary disease, obesity, hyperfiltration, donor-related nephrosclerosis, and CNI-induced arteriolopathy. In the case of nephrotic syndrome after kidney transplantation, we should consider not only recurrent FSGS, but also CNI-induced nephrotoxicity to determine the optimal treatment.

The First Case Report of the Treatment of Transplant Coronary Artery Disease With Dextran Sulfate Adsorption Lipid Apheresis

In patients who have undergone a heart transplant, the major cause of death is coronary artery disease (CAD). The etiology of cardiac-allograft vasculopathy is thought to be multifactorial, but due in large part to immune mechanisms that cause elevations in serum cholesterol levels. The dextran sulfate cellulose low-density lipoprotein (LDL) adsorption (DSA) apheresis procedure has been shown to reduce lipoprotein levels and markers of blood rheology to improve coronary perfusion to the transplanted heart. We report the first described case of the stabilization and reversal of progressive transplant CAD with DSA. We followed a 50-year-old male orthotopic heart transplant recipient with familial hyperlipidemia refractory to lipid lowering therapy with bi-weekly LDL-apheresis (DSA system) for 12 months. Quarterly pre- and post-apheresis blood investigations were obtained, as well as annual adenosine thallium (AT) studies. Creatinine kinase (CPK), creatinine, LDL, fibrinogen, and lipoprotein (a) were reduced by 70%, 26%, 23%, 47%, and 47%, respectively. AT before the initiation of apheresis revealed a small to medium sized, partially reversible perfusion defect in the anterolateral and inferoapical walls, with an ejection fraction (EF) of 49%, elevated left ventricular volume (171 mL), and an elevated pulmonary-to-myocardial (PMR) count ratio of 0.67 (normal <0.52). After 12 months of LDL apheresis with DSA, a repeat AT demonstrated no fixed or reversible perfusion abnormality, an EF of 51%, and the PMR had normalized (0.46). This is the first reported case demonstrating that in a heart transplant survivor with hyperlipidemia and progression of coronary artery disease, LDL apheresis with DSA therapy can lead to regression and is an effective treatment of post-transplant coronary disease.

Low‐Density Lipoprotein Apheresis Decreases Ferritin, Transferrin and Vitamin B12, Which May Cause Anemia in Serially Treated Patients

Clinical observations revealed an increased prevalence of iron deficiency anemia without chronic bleeding in patients treated with serial low-density lipoprotein (LDL) apheresis. Since several different proteins are adsorbed by LDL apheresis beside pro-atherogenic lipoproteins, we examined the modification of the full blood count, plasma iron, vitamin B12, folic acid, and hemolysis by LDL apheresis. Nineteen patients (55 (50-59) years, 4 female, 15 male) undergoing chronic LDL apheresis due to mixed dyslipidemia (N = 17), homozygous familiar hypercholesterolemia (N = 1) or isolated elevated lipoprotein(a) (N = 1) were included in this study. They were treated with direct adsorption of lipoproteins (DALI; N = 6), heparin-induced LDL-precipitation (HELP; N = 7) or double filtration plasmapheresis (DFPP; N = 6). The patients' full blood count, iron metabolism (plasma iron, ferritin, transferrin, transferrin saturation), vitamins involved in erythropoiesis (vitamin B12 and folic acid), and markers of hemolysis (haptoglobin and free hemoglobin) were analyzed directly before and after LDL apheresis. A single LDL apheresis session significantly decreased the levels (reduction in the median [25(th)-75(th) percentiles] of: ferritin 9.8 [1.3-18] %; P = 0.004), transferrin (12.1 [10.0-15.96] %; P = 0.0005), and vitamin B12 (17.8 [16.2-20.8] %; P = 0.0005). Thereby, transferrin and vitamin B12 were decreased in all (N = 19) and ferritin in 74% (N = 14) of the patients. Twelve out of 19 patients (63.2%) had mild anemia despite iron administration in 14 out of 19 patients (73.7%). LDL apheresis had no significant influence on full blood count, plasma iron, transferrin saturation, folic acid, or hemolysis. Similar changes were observed in all LDL apheresis methods used. LDL apheresis significantly decreases ferritin, transferrin, and vitamin B12, suggesting an influence of serial LDL apheresis on erythropoiesis.

Retrospective Analysis of Long‐term Lipid Apheresis at a Single Center

We retrospectively analyzed 10 906 lipid apheresis sessions (heparin-induced lipoprotein precipitation, direct adsorption of lipoproteins, double filtration plasmapheresis, dextran sulfate adsorption, and immunoadsorption) in 38 patients who were consecutively treated in our department during the last 20 years. The incidences of major cardiovascular events (MACE) (death, cerebrovascular accident, myocardial infarction, limb amputation, and renal vascular involvement) were taken separately as primary end-points or as a combined end-point. The time-course of secondary end-points (coronary and extracranial status of arteries, left ventricular function, occlusive artery disease, and calculated glomerular filtration rate [cGFR]) were also evaluated, as well as the extent of the reduction in plasma lipids and lipoproteins and the incidence of therapy associated side-effects. MACE decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis and the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year. Classical (diabetes mellitus, arterial hypertension, and smoking history), as well as novel risk factors (cGFR < 60 mL/min, statin withdrawal, mixed hyperlipoproteinemia, and elevated lipoprotein (a)) were associated with an elevated risk for MACE. All applied methods had comparable effects. All lipid apheresis methods proved to be safe and suitable for long-term treatment. The present data demonstrate that treatment with lipid apheresis is very effective and leads to long-term reduction in cardiovascular mortality and morbidity.