Low-density lipoprotein apheresis for focal glomerular sclerosis.

We report on a 22-year-old female with focal glomerular sclerosis and hyperlipidemia who did not respond to long-term steroid or immunosuppressant therapy. When low-density lipoprotein (LDL) apheresis was performed, her total daily protein excretion decreased, serum albumin increased, total cholesterol decreased from 1,052 mg/dl to 148 mg/dl after 3 months, and the serum lipoprotein(a) level also decreased from 117.8 mg/dl to 9.1 mg/dl. After this therapy, her clinical course was well maintained. By controlling hyperlipidemia, including oxidized low-density lipoprotein and lipoprotein(a), low-density lipoprotein apheresis may produce clinical improvement in focal glomerular sclerosis.     

Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia

The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice.     

Low-density lipoprotein apheresis for prevention and regression of atherosclerosis: clinical results.

Hypercholesterolemia can be adequately controlled by appropriate diet and maximum lipid lowering drug therapy in most patients. Nevertheless, there exists a group of patients, including those with familial hypercholesterolemia (FH), who remain at high risk for the development or progression of premature coronary heart disease (CHD). For these patients additional measures such as surgery and low-density lipoprotein (LDL) apheresis have to be considered. The objective of this multicenter trial, which included 30 clinical centers (28 in Germany and one each in Scotland and Luxembourg), was to determine if repeated LDL apheresis using the Liposorber LA-15 system (Kaneka Corporation, Osaka, Japan) could lead to an additional acute and time averaged lowering of total cholesterol (TC) and LDL-cholesterol (LDL-C) in severely hypercholesterolemic patients whose cholesterol levels could not be controlled by appropriate diet and maximum drug therapy. A total of 6,798 treatments were performed on 120 patients, including 8 with homozygous FH, 75 with heterozygous FH, and 37 with unclassified FH or other hyperlipidemias from 1988 through 1994. The mean TC and mean LDL-C levels at baseline were 410.0 mg/dl and 333.9 mg/dl, respectively. LDL apheresis was performed once a week or at least once every 2 weeks in all patients. During treatment with the Liposorber system the mean acute percentage reduction was 52.6% for TC and 63.1% for LDL-C. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were also substantially reduced to 60.6% and 47.5%, respectively. Fibrinogen, a potential risk factor for CHD, was reduced by 26.2%. In contrast, the mean acute reduction of high density lipoprotein (HDL) was only 3.4%. During the course of the treatment, the time averaged levels of TC and LDL-C were reduced by approximately 39% and 50%, respectively, compared to baseline levels. The adverse events (AEs) were those generally associated with extracorporeal treatments. The most common AE was hypotension, with 69 episodes corresponding to 1% of all treatments reported in 44 of the 120 patients treated. All other kinds of AEs occurred in less than 0.2% of the treatments. The treatment with the Liposorber LA-15 system was overall well tolerated. It should be noted, however, that a more severe type of hypotensive reaction associated with flush, bradycardia, and dyspnea was reported in patients taking concomitant angiotensin converting enzyme (ACE) inhibitor medication. Except for such anaphylactoid-like reactions associated with the intake of ACE inhibitors, the Liposorber LA-15 system represents a safe and effective therapeutic option for patients suffering from severe hypercholesterolemia that could not be adequately controlled by diet and maximum drug therapy.     

Acute changes in plasma levels of hepatocyte growth factor during low-density lipoprotein apheresis.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor, and angiogenesis is included in a variety of its functional effects. HGF levels were measured in 5 sessions of low-density lipoprotein (LDL) apheresis in 3 patients with severe hypercholesterolemia. Blood was collected at the start (T0) and at 1,000 ml (T1), 2,000 ml (T2), and 3,000 ml (T3) plasma treatments. During LDL apheresis, HGF levels increased from 1.59 +/- 0.78 (mean +/- SE, n = 5) ng/ml at T0 to 6.64 +/- 0.97 at T1, 6.28 +/- 0.97 at T2, and 5.20 +/- 0.94 at T3. In one apheresis session, HGF increased immediately at the 100 ml plasma treatment stage. HGF was adsorbed completely by a dextran-sulfate (DS) column. Despite the adsorption by the DS column, HGF in the patient blood increased to the levels with functional effects. The improvement of ischemic symptoms due to LDL apheresis may be related to the angiogenic activities of HGF.     

Low-density lipoprotein apheresis using the Liposorber system: features of the system and clinical benefits.

LDL apheresis using the Liposorber system is indicated for use to remove selectively LDL from the plasma of hypercholesterolemic patients for whom diet and maximum cholesterol-lowering drug therapy have been ineffective or not tolerated. The dextran sulfate immobilized to porous cellulose beads is contained in the adsorption column as the adsorbent. The dextran sulfate has a structure similar to that of the LDL receptor and seems to act as a type of pseudoreceptor for LDL. There have been reported a number of clinical benefits using the Liposorber system for drug refractory hypercholesterolemic patients. Among them, the improvement of endothelial cell function of coronary and brachial arteries by a single treatment is the focus of the world's attention. Moreover, it is also noteworthy that LDL apheresis reduced the incidence of the cardiac events by 70% compared to drug therapy alone. In addition to the clinical benefits of the Liposorber system on familial hypercholesterolemia (FH), the preliminary data suggest that LDL apheresis may improve arteriosclerosis obliterans (ASO) of the lower extremities and focal glomerular sclerosis (FGS).     

Changes in plasma levels of cyclic nucleotides during low-density lipoprotein apheresis.

The negative charges of dextran sulfate (DS) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by the production of bradykinin. This study was undertaken to see whether cyclic nucleotide plasma levels are affected by DS LDL apheresis. Previously, we showed the rise in plasma levels of prostaglandins and nitric oxide derivatives accompanied by the rise in bradykinin levels. The physiologic effects of prostaglandins and nitric oxide become manifest through the intracellular signal of cyclic nucleotides. The plasma levels of the cyclic nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. The plasma levels of cAMP during LDL apheresis using heparin were 9.2 +/- 0.3 (mean +/- SE) 12.4 +/- 0.6, 12.0 +/- 0.5, and 12.1 +/- 0.3 pmol/ml, respectively, at the 0, 1,000, 2,000, and 3,000 ml stages. The rise in cAMP levels was suppressed during apheresis using NM. There were no significant increases in cGMP during apheresis with heparin or with NM. There were significant negative correlations between changes in cAMP and those in the blood pressure. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects via activation of the adenylate cyclase dependent pathway.     

Changes in plasma levels of nitric oxide derivative during low-density lipoprotein apheresis.

The negative charges of dextran-sulfate (DS) used for low-density lipoprotein (LDL) apheresis activates the intrinsic coagulation pathway, in which plasma kallikrein acts on high-molecular-weight kininogen (HMWK) to produce large amounts of bradykinin. This study was undertaken to see whether bradykinin generated during DS LDL apheresis has some physiologic effects in vivo. The plasma levels of bradykinin and nitric oxide derivatives (NOx) were examined when either of 2 anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity, this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the marked increase in bradykinin levels (before apheresis, 18 +/- 3 (mean +/- SE, n = 5) pg/ml; after apheresis 470 +/- 140, p < 0.01) was associated with the increase in NOx (before apheresis 50 +/- 11 pg/ml; after apheresis 66 +/- 15). Interestingly, these changes in bradykinin and NOx levels were suppressed during apheresis using NM. The changes in plasma NOx levels were negatively correlated with those in blood pressures. These findings suggest that bradykinin generated during apheresis exerts some physiologic effects by means of activation of endothelium-derived relaxant factor (EDRF). Our results support the view that bradykinin produced during DS LDL apheresis has physiologic significance.     

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 ± 6.4 vs. 13.1 ± 0.3 mg kg^–1 day^–1; P  < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 ± 0.04 vs. 0.33 ± 0.008 pools day^–1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate ( R  = –0.82; P  < 0.05). Plasma lipoprotien (a) [Lp(a)] levels were significantly ( P  < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate ( R  = 0.90; P  < 0.01), VLDL-cholesterol ( R  = 0.95; P  < 0.001) and VLDL-triglycerides ( R  = 0.80; P  < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.     

Current topics on low-density lipoprotein apheresis.

The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lp[a]) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL-apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL-adsorption, and LDL-hemoperfusion. Despite substantial progress in diagnostics, drug therapy, and cardiosurgical procedures, atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia (HLP) therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, however, sometimes the goal of therapy cannot be reached. Mostly, the prognosis of patients suffering from severe HLP, sometimes combined with elevated Lp(a) levels and CHD refractory to diet and lipid-lowering drugs is poor. Hence, in such patients, treatment with LDL-apheresis can be useful. Regarding the different LDL-apheresis systems used, there were no significant differences with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein, or triglyceride concentrations. With respect to elevated Lp(a) levels, however, the immunoadsorption method seems to be the most effective. The published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application.     

Low-density lipoprotein apheresis using the liposorber dextran sulfate cellulose system for patients with hypercholesterolemia refractory to medical therapy

A subset of patients with familial hypercholesterolemia (FH) have an inadequate lipid-lowering response to diet and drug treatment and should be considered for low-density lipoprotein (LDL)-apheresis therapy. This procedure selectively removes apolipoprotein B-containing particles [LDL, very-low-density lipoprotein, lipoprotein(a)] from plasma independent of diet and drug therapy. Methods for performing LDL-apheresis include dextran sulfate cellulose adsorption, immunoadsorption, and heparin-induced extracorporeal precipitation. The Liposorber Study Group evaluated LDL removal using the Liposorber® LA-15 LDL-apheresis System in 64 patients with FH who had not responded adequately to diet and maximal drug therapy. Mean acute reductions in LDL cholesterol (LDL-C) were 76% in heterozygous FH (HtFH) patients and 81% in homozygous FH (HoFH) patients. Time-averaged levels of LDL-C were lowered 41% in HtFH and 53% in HoFH patients. Hypotension was the most frequent side effect, occurring in 3% of procedures. The Liposorber® LA-15 System has been approved by the Food and Drug Administration and is recommended for 1) patients with functional homozygous FH (LDL-C level >500 mg/dL; 2) patients with coronary artery disease (CAD) and LDL-C levels ≥200 mg/dL; 3) patients without CAD, but an LDL-C level ≥300 mg/dL. © 1996 Wiley-Liss, Inc.     

Efficacy of different low-density lipoprotein apheresis methods.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary heart disease and drug resistant hypercholesterolemia. Various apheresis systems based on different elimination concepts are currently in use. We compared the efficacy of 4 different apheresis systems concerning the elimination of lipoproteins. The study included 7 patients treated by heparin extracorporeal LDL precipitation (HELP), 10 patients treated by immunoadsorption, 8 patients treated by dextran-sulfate adsorption, and 4 patients treated by cascade filtration. Ten subsequent aphereses were evaluated in patients undergoing regular apheresis for more than 6 months. Total cholesterol decreased by approximately 50% with all 4 systems. LDL cholesterol (LDL-C) (64-67%) and lipoprotein a [Lp(a)] (61-64%) were decreased more effectively by HELP, immunoadsorption, and dextran-sulfate apheresis than by the less specific cascade filtration system [LDL-C reduction 56%, Lp(a) reduction 53%]. Triglyceride concentrations were reduced by 40% (dextran-sulfate) to 49% (cascade filtration) and high-density lipoproteins (HDL) by 9% (dextran-sulfate) to 25% (cascade filtration). On the basis of plasma volume treated, HELP was the most efficient system (LDL-C reduction 25.0%/L plasma), followed by dextran-sulfate (21.0%/L plasma), cascade (19.4%/L plasma), and immunoadsorption (17.0%/L plasma). However, a maximal amount of 3 L plasma can be processed with HELP due to concomitant fibrinogen reduction while there is no such limitation with immunoadsorption. Therefore, the decision of which system should be used in a given patient must be individualized taking the pre-apheresis LDL concentration, concomitant pharmacotherapy, and fibrinogen concentration into account.     

Effects of losartan on low-density lipoprotein apheresis.

The negative charges of dextran sulfate cellulose (DSC) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by bradykinin production. This study was undertaken to see whether an antagonist of angiotensin receptor (AT1), losartan, could be safely used in a patient treated by DSC-LDL apheresis. Losartan (50 mg/day) was given to a patient with coronary heart disease who had been treated by DSC-LDL apheresis and had experienced an anaphylactoid reaction by administration of an angiotensin converting enzyme inhibitor. The effects of losartan on blood pressures and humoral factors were examined by comparing these parameters between apheresis with and without losartan. Blood pressures and plasma levels of bradykinin, renin, and aldosterone were measured before and at 1,000, 2,000, and 3,000 ml of plasma treatment. Bradykinin levels during LDL apheresis tended to be higher with losartan than without losartan (without versus with, 529 +/- 121 [n = 4, mean +/- SE] pg/ml vs. 1,058 +/- 49 at the 2,000 ml stage, p < 0.01). The rise of plasma renin activity with losartan (221 +/- 26% at the 3,000 ml stage) was significantly greater than that without losartan (144 +/- 2.4%). Mean blood pressure decreased by 7% during apheresis with losartan, but blood pressure reduction was not accompanied by any complaints. These results suggest that AT1 receptor antagonists are safely used in patients treated by DSC-LDL apheresis.     

Low-density lipoprotein size and cardiovascular risk assessment

Q J Med 2006; 99:1–14. The authors     

Low-density lipoprotein size and cardiovascular risk assessment

A predominance of small, dense low-density lipoproteins (LDL) has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. LDL size seems to be an important predictor of cardiovascular events and progression of coronary heart disease and evidences suggests that both quality (particularly small, dense LDL) and quantity may increase cardiovascular risk. However, other authors have suggested that LDL size measurement does not add information beyond that obtained by measuring LDL concentration, triglyceride levels and HDL concentrations. Therefore, it remains debatable whether to measure LDL particle size in cardiovascular risk assessment and, if so, in which categories of patient. Therapeutic modulation of LDL particle size or number appears beneficial in reducing the risk of cardiovascular events, but no clear causal relationship has been shown, because of confounding factors, including lipid and non-lipid variables. Studies are needed to investigate the clinical significance of LDL size measurements in patients with coronary and non-coronary forms of atherosclerosis; in particular, to test whether LDL size is associated with even higher vascular risk, and whether LDL size modification may contribute to secondary prevention in such patients.     

The effect of selective low-density lipoprotein apheresis on plasma lipoperoxides and antioxidant vitamins in familial hypercholesterolemic patients.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by a lifelong elevation in the concentration of low-density lipoprotein (LDL) bound cholesterol in blood by cholesterol deposits and by early coronary artery disease. The LDL apheresis technique has been introduced with the goal of reducing LDL cholesterol levels, thereby preventing the development of atherosclerosis. The literature on LDL apheresis reports 2 different facets, the therapeutic aspect associated with the lessening of LDL concentration and the initiation of a peroxidation process associated with the biocompatibility of the artificial membrane. Lipid and protein peroxidation gives rise to toxic and atherogenic hydroperoxide, mostly lipid hydroperoxides, and derivative compounds, which may offset the benefit of the procedure. In this paper, plasma hydroperoxide levels are determined along with the elevation of the serum and LDL antioxidant status in hypercholesterolemic patients before and following repeated LDL apheresis sessions. Hydroperoxide concentration has been expressed both in terms of plasma volume and LDL concentration. A highly significant increase in LDL lipid hydroperoxides is demonstrated when expressed in terms of LDL concentration and is associated with the LDL apheresis procedure. The usefulness of antioxidant supplementation in LDL apheresis is discussed.     

Low-density lipoprotein subclass and its correlating factors in diabetics

OBJECTIVES: Small dense LDL, low density lipoprotein (LDL) particles with small size and high density, is regarded as a significant risk factor for cardiovascular diseases. Diabetes mellitus is one of the conditions accompanied by increased small dense LDL. We analyzed LDL subclass in type 2 diabetics and normal controls with LipoPrint LDL System to investigate the LDL heterogeneity in diabetics and factors affecting it. DESIGN AND METHODS: We selected 40 normal controls and 40 type 2 diabetics with fasting blood glucose level over 7.0 mmol/L and HbA1c level over 7%. LDL subclass was determined with LipoPrint LDL System. LipoPrint LDL System fractionates LDL into seven parts (LDL1-7) by size and LDL3 to LDL7 are defined as small-sized LDL. In addition we estimated 'the percent of small-sized LDL over whole LDL' and defined it as 'small-sized LDL proportion'. RESULTS: Mean small-sized LDL proportion was significantly higher in diabetics (23.4%) than in controls (11.8%) (p<0.001) and small-sized LDL proportion showed positive correlation with blood levels of glucose, HbA1c, total cholesterol, triglyceride, and oxidized LDL and negative correlation with HDL cholesterol level in univariate analysis (p<0.001). Of these parameters, triglyceride, HbA1c, oxidized LDL were statistically significant variables contributing to the small-sized LDL proportion in stepwise multiple regression analysis. CONCLUSIONS: We analyzed small-sized LDL proportion in type 2 diabetics and found that it was significantly increased in diabetics than control subjects and it was independently correlated with triglyceride, HbA1c, oxidized LDL in descending order, which are reflecting lipid metabolism, glycation, and oxidative stress, respectively.     

Dextran sulfate (Selesorb) plasma apheresis improves vascular changes in systemic lupus erythematosus.

Apheresis has been effective as rescue therapy in patients with severe, therapy-resistant, systemic lupus erythematosus (SLE). Its benefit in patients with less severe but therapy-resistant SLE is not known. Dextran sulfate apheresis was applied as a rescue therapy for therapy-resistant vasculitic skin lesions in a 30 year old female patient with a 9 year history of SLE in combination with antiphospholipid syndrome and Raynaud's phenomenon. Partial remission was achieved after 9 immunoadsorption sessions, as documented by marked improvement of skin lesions and an increase of capillary density in the nailfold area. Further improvement was noted with maintenance therapy using mycophenolate mofetil. Dextran sulfate apheresis can be applied safely in patients with moderate therapy-resistant SLE disease activity when severe immunodeficiency and cytotoxic adverse effects should be avoided.