Therapeutic apheresis in the treatment of hemolytic uremic syndrome in view of pathophysiological aspects

Hemolytic-uremic syndrome (HUS) is a disease that can lead to acute kidney injury and often to other serious sequelae, including death. The disease is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In view of the different courses of HUS, a minimum of three different pathogenetic types leading to HUS can be subdivided as follows: HUS caused by infection, idiopathic HUS (non-Shiga toxin HUS), and HUS in systemic diseases and after toxin exposure. The etiology and pathogenesis of HUS are not completely understood and its therapy is complicated. After the introduction of therapeutic apheresis as a supportive therapy in HUS, several authors reported successful treatment in more than 87% of treated patients. The supportive therapy is indicated basically in severe courses of HUS and is superior to available therapy interventions.     

Therapeutic Apheresis in Immunologic Renal and Neurological Diseases

Since the mid 1970s, when membrane modules became available, plasma separation techniques have gained in importance especially in the past few years. The advantages of this method are a complete separation of the corpuscular components from the plasma and due to increased blood flow rate and higher efficacy. Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a poor prognosis without treatment. Therapeutic apheresis (TA) in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 40 years. The updated information on immunology and molecular biology of different immunologic diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different diseases can be treated by various apheresis methods such as therapeutic plasma exchange (TPE) with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non‐biological agents. Here, the authors provide an overview of the most important pathogenic aspects indicating that TA can be a supportive therapy in systemic autoimmune diseases such as renal and neurological disorders. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Committee of the American Society for Apheresis are cited.     

Therapeutic Apheresis in Hematologic,Autoimmune and Dermatologic Diseases With Immunologic Origin

The process of curing a patient by removing his illness by extracting blood is a very old one. Many years ago, phlebotomy was practiced to cure illness. Now, this old process, placed on a rational basis with therapeutic apheresis (TA), is being followed in clinical practice. Therapeutic plasma exchange (TPE) with hollow fiber modules has been used in different severe diseases for more than 40 years. Based on many years of experience with the extracorporeal circulation in end‐stage renal disease, the authors herein give an overview of TA in immunological diseases, especially in hematologic, autoimmune and dermatologic diseases. Updated information on immunology and molecular biology of different immunological diseases is discussed in relation to the rationale for apheresis therapy and its place in combination with other modern therapies. With the introduction of novel and effective biologic agents, TA is indicated only in severe cases, such as in rapid progression despite immunosuppressive therapy and/or biologic agents. In mild forms of autoimmune disease, treatment with immunosuppressive therapies and/or biologic agents seems to be sufficient. The prognosis of autoimmune diseases with varying organ manifestations has improved in recent years, due in part to very aggressive therapy schemes. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Applications Committee of the American Society for Apheresis are cited. TA has been shown to effectively remove the autoantibodies from blood and lead to rapid clinical improvement.     

Autoantigen estimation and simple screening assay against cardiodepressant autoantibodies in patients with dilated cardiomyopathy

The objective of this study was to identify the cardiodepressant autoantibodies that could directly influence left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy (DCM), as well as to establish a simple screening method for these antibodies. Not only acute hemodynamic but also chronic prognosis improvements were reported with immunoadsorption in some patients with DCM. Various antibodies determined by immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (beta1-adrenergic [beta1-] receptors, muscarinic M2-acetylcholine [M2-] receptors, troponin I, or Na-K-ATPase) were measured in 104 patients with DCM. Cardiodepressant antibodies were also determined by ultrasonic echocardiography (UCG) of 18 day old chick embryos after adding the patients' purified immunoglobulin G, and the following clinical features were compared: age, gender, New York Heart Association class, LVEF, neurohumoral factors, arrhythmias, and other antibodies. We also checked the in vitro immunoadsorption effect against these cardiodepressant antibodies. Cardiodepressant antibodies were found in 63% of 104 patients with DCM and had no relation to other clinical parameters, except for some antibodies such as anti-beta1-receptor antibodies (81% vs. 52%, P < 0.01), anti-M2-receptor antibodies (83% vs. 48%, P < 0.01), or anti-Na-K-ATPase antibodies (85% vs. 55%, P < 0.01). However, cardiodepressant antibodies were similarly found in patients with and without antibodies against troponin I (56% vs. 64%). The LVEF of chick embryos measured by UCG in the presence of patient serum was improved after in vitro immunoadsorption. The ex vivo system using chick embryos was able to determine cardiodepressant antibodies. By multivariate analysis, antibodies against beta1- or M2-receptors was a predictor of these autoantibodies.     

Combination of Therapeutic Apheresis and Therapeutic Ventricular Assistance for End‐Stage Heart Failure Patients

Abstract: Dilated cardiomyopathy is a cardiac disease of unknown origin which is characterized by the gradual development of cardiac failure associated with four‐chamber dilatation of the heart. Heart transplantation has been considered as the last resort for this disease. However, some patients who received support with a ventricular assist device (VAD) as a bridge‐to‐transplantation and then recovered without transplantation have been reported. This new concept of treating heart failure is termed bridge‐to‐recovery. A VAD can inhibit the heart failure compensatory mechanisms by extreme ventricular unloading. Also, heart failure is a complex neurohormonal/autocrine‐paracrine syndrome, and these mechanisms consecutively lead to inflammatory response by proinflammatory cytokines; interleukin‐1α (IL‐1α), interleukin‐1β (IL‐1β), interleukin‐2 (IL‐2), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). Furthermore, the existence of anti‐β₁‐adrenoceptor autoantibodies (A‐β₁‐AABs) in a patient with dilated cardiomyopathy has been reported. These proinflammatory cytokines and this antibody accelerate a ventricular remodeling and a contractile dysfunction over the long term. Apheresis can also inhibit the vicious cycle in heart failure by removing the factors that are produced by activated neurohormonal/autocrine‐paracrine compensatory mechanisms. Therefore, we propose that the combined therapies, therapeutic VAD and therapeutic apheresis, will provide a prominent outcome for a patient who is suffering from end‐stage heart failure.     

Extracorporal low-density lipoprotein elimination by immunoadsorption

Low-density lipoprotein (LDL) apheresis has proven its therapeutic usefulness in patients who suffer from coronary heart disease but cannot achieve LDL cholesterol concentrations defined by the National Cholesterol Education Program guidelines. Immunoadsorption was the first commercially available apheresis technique. It is based on affinity chromatography. As with other apheresis techniques, immunoadsorption has specific advantages and disadvantages. These have to be taken into account when selecting an apheresis technique for the individual patient.     

Apheresis technologies and clinical applications: the 2005 International Apheresis Registry

The developments in apheresis technologies and techniques and their clinical applications worldwide are technologically, sociologically, and economically motivated. In past apheresis surveys the statistics have highlighted both the differences by geographic region in clinical practice and in the types of technologies utilized. While a national view of apheresis is very important, an international view may be more representative overall of this therapeutic modality than national results that are highly dependent on the local economics and the available technologies. These regional differences have provided a basis for scientific and clinical assessment of these apheresis technologies and their clinical outcomes, and have impacted the marketing and business developments of new technologies worldwide. The results of the International Apheresis Registry for 2005 reporting from 22 centers on 5 continents are presented. The survey collected data exclusively via a secure internet website on 1133 patients for a total of 6501 treatments. Unlike our prior registries, information on stem cell infusions was gathered. Information gathered included patient demographics, medical history, treatment diagnoses, treatment specifics (type, methodology, access type, anticoagulants, drugs, and equipment usage), side-effects, clinical response, and payment provider. As in the prior International Apheresis Registries for 1983, 2000, and 2002 the survey results highlight the regional differences in apheresis usage and treatment methodologies, indicating that an international overview of apheresis may be more representative of the impact of this therapeutic modality.     

Apheresis of Immune Diseases and Apheresis Using Immunological Specificity

Abstract: It has been clearly shown that autoimmune diseases can be treated by apheresis by eliminating immune complexes, however, the effects of therapeutic apheresis are not limited to immune disorders. Almost all diseases are associated with immune systems. Immune systems can be regulated by advanced techniques of apheresis, including immunoadsorption and immunocytapheresis, removing immune effector molecules and various immune‐associated cells selectively. Therefore, apheresis can be used as a nondrug treatment for many diseases. In addition, disease‐associated proteins that cause disease or are produced in the course of diseases and accumulate in the body could be eliminated selectively by apheresis using the extremely powerful ability of the immune system to recognize polypeptide structures specifically and distinguish miniscale differences among molecules. In this article, we discuss the current status of treatment of immune diseases by apheresis and possible treatment approach of a variety of diseases by apheresis based on immune reactions.     

State of the art of low-density lipoprotein apheresis in the year 2003

Low-density lipoprotein (LDL) apheresis is a last-resort treatment for hypercholesterolemic patients resistant to conservative lipid-lowering therapy. In the extracorporeal circuit, LDL, Lp(a) and coagulation factors are selectively eliminated, while the beneficial proteins like high-density lipoprotein, albumin and immunoglobulins are returned to the patient. Clinical effects of LDL apheresis comprise improvement of symptoms like angina and exercise tolerance, reduction of clinical coronary events like unstable angina, need for angioplasty or bypass operation, myocardial infarction and ultimately coronary mortality. The reduction of atherogenic lipoproteins and of coagulation factors by LDL apheresis (LA) positively influences hemorheology, endothelial function and coronary reserve. In the controlled LAARS, LA significantly improved the electrocardiographic signs of myocardial ischemia in the treadmill test. In angiographically controlled trials such as LARS and L-CAPS, a reduction of progression of coronary lesions was observed; in favorable cases, regression of the stenoses could be documented. In addition, in the LDL apheresis coronary morphology trial, LA decreased the coronary plaque area. The Hokuriku trial documented a 72% decrease of coronary events (MACE) in the LA group vs. controls treated only by statins. In longitudinal studies, the incidence of MACE after regular LA decreased compared with the preapheresis period in the same patients. Apart from coronary heart disease, recent studies indicate a positive effect of LA also on carotid artery stenoses and peripheral vascular disease. Prospective randomized studies showed the beneficial effects of cascade filtration on age-related macular degeneration and of heparin-induced LDL precipitation apheresis on acute inner ear deafness.     

Physical Principles in Therapeutic Apheresis

Abstract: Physical modality could have some impact on new apheresis technologies because it is nonbiologic and controllable for its operating conditions. In this article, the application of electromagnetic force and light scattering force to bioseparation and biostimulation was explored.     

Low-density lipoprotein apheresis: an overview

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. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) 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. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement in general well-being and increased performance were experienced by 44 of 45 patients. The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application.     

Three Cases of C‐ANCA‐Positive Vasculitis Treated with Immunoadsorption: Possible Benefit in Early Treatment

Abstract: Wegener's granulomatosis is a vasculitic disease predominantly affecting the upper respiratory tract, lungs, and kidneys. Three patients with Wegener's granulomatosis and rapidly progressive glomerulonephritis were treated with an intensified regimen of immunoadsorption (IA) (Excorim or Therasorb) in addition to cyclophosphamide (CYC) and methylprednisolone (PRE). Patient A had been in remission under oral CYC/PRE. The first exacerbation was treated successfully with 4 IA treatments without changing medication. Patient B experienced 3 flares within 1 year, which were treated with 28 IA (3–7 IAs/course), intravenous CYC after each course, and PRE. A fall of creatinine levels from 120 to 190 μmol/L to 100 μmol/L was noted after IA and before administration of CYC. Patient C presented in uremia. Autoantibodies were eliminated by 11 IA treatments parallel to CYC/PRE therapy. They remained within a normal range for >1 year's follow‐up; however, kidney function did not return. In conclusion, the observations in Patients A and B suggest a beneficial therapeutic effect of early IA in WG.     

Direct Adsorption of Lipoproteins from Whole Blood by DALI Apheresis: Technique and Effects

Abstract: Low‐density lipoprotein (LDL) apheresis can drastically reduce atherogenic lipoproteins in coronary patients in whom LDL and lipoprotein (a) (Lp[a]) cannot be sufficiently reduced by conservative therapy. LDL and Lp(a) adsorption by polyacrylate/polyacrylamide (DALI) is the simplest procedure for clinical LDL apheresis to date. DALI was first applied in patients in 1994 and introduced into clinical routine in 1996. It is the first LDL‐hemoperfusion system, i.e., it adsorbs LDL and Lp(a) directly from whole blood. This markedly simplifies the extracorporeal circuit, the handling of the system, and reduces significantly staff time and, especially at higher blood flow rates, treatment time. Its features are high selectivity and capacity of lipoprotein removal (maximum about 8 g low‐density lipoprotein cholesterol per session). Using citrate anticoagulation, good biocompatibility is evidenced by the lack of cell losses, hemolysis, thrombotic events, and complement activation. Some clotting factors of the intrinsic system are also adsorbed. There is significant bradykinin activation that, however, does not cause problems in most patients if angiotensin converting enzyme inhibitor medication is avoided. In a first long‐term study, 93% of sessions were uneventful. Major side effects were citrate‐induced paresthesias (1.3%) and hypotension (0.8%). To date, more than 25,000 DALI sessions have been performed all over the world.     

Direct adsorption of low-density lipoprotein by DALI-LDL-apheresis: results of a prospective long-term multicenter follow-up covering 12,291 sessions

Direct adsorption of lipoproteins (DALI) is the first low density lipoprotein (LDL)-apheresis technology by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present follow-up was carried out to evaluate the clinical efficacy, selectivity and safety of long-term DALI apheresis. The follow-up was carried out in an open, prospective uncontrolled multicenter clinical design. Included were 158 drug-resistant hypercholesterolemic patients from 28 apheresis centers. These patients underwent 12 291 DALI sessions between January 1997 and March 2002. The patients suffered from severe atherosclerosis and their mean LDL-C was 188 mg/dL before the sessions. Mean follow-up was 25 +/- 16 (range 1-56) months during which 78 +/- 53 sessions were carried out. In most treatments, DALI 750 (63%) or DALI 1000 (30%) adsorbers were used. On average, 7423 +/- 1495 mL blood was processed at a flow rate of 84 +/- 16 mL/min in 102 +/- 25 min. Acute reductions by the single DALI sessions averaged 69 +/- 12% for LDL-C, 41 +/- 18% for TG, 15 +/- 10% for HDL-C, 19 +/- 11% for fibrinogen and 62 +/- 24% for Lp(a) (in patients with Lp(a) > 30 mg/dL). Adverse events were recorded in only 3.9% of the sessions. In this 5-year follow-up, long-term therapy with DALI was safe, effective and selective as LDL-C and Lp(a) could be reduced by >60% per session in approximately 100 min treatment time while HDL-C decrease and the incidence of AE were low.     

Changes in C-reactive protein plasma levels during low-density lipoprotein apheresis

C-reactive protein (CRP) is one of the important risk factors for atherosclerosis, and its serum level is lowered by popular cholesterol-lowering drugs, statins. This study was undertaken to examine the changes of CRP levels during dextran-sulfate (DS) low-density lipoprotein (LDL) apheresis. In 15 apheresis sessions in seven patients with severe hypercholesterolemia (four men and three women, aged between 36 and 70 years), changes in CRP levels were examined. The efficiency in adsorption of CRP with DS column was evaluated by measuring CRP levels in both pre- and post-column plasma. In one patient, the effect of repeated apheresis sessions on CRP preapheresis levels was examined. The changes in interleukin (IL)-6 plasma levels were also examined in six sessions. Although IL-6 levels after 3,000 mL-plasma treatment rose to 170% of preapheresis levels, CRP levels decreased significantly (from 1.91 +/- 0.49 mg/L to 0.89 +/- 0.24, P < 0.01). C-reactive protein was almost completely adsorbed by the DS column and CRP preapheresis levels were decreased gradually by repetition of apheresis. CRP, a novel risk factor of atherosclerosis, was effectively removed by DS-LDL apheresis. The decrease in CRP plasma levels may be involved in prevention of atherosclerotic vascular diseases due to DS-LDL apheresis.     

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid‐lowering therapies

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)‐cholesterol. Standard lipid‐lowering drugs and LDL‐apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL‐apheresis and transplantation, but long‐term safety and efficacy data are lacking for all of these options.     

Rheopheresis for Age‐Related Macular Degeneration: A Novel Indication for Therapeutic Apheresis in Ophthalmology

Abstract: Age‐related macular degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly. Successful therapy is not yet available for the majority of patients, especially not for patients with dry AMD. AMD at cellular and molecular levels is at least in part a microcirculatory disorder of the retina. Rheopheresis is a safe and effective modality of therapeutic apheresis to treat microcirculatory disorders and represents a novel treatment option for patients with dry AMD. Elimination of a defined spectrum of high molecular weight proteins from human plasma including pathophysiologically relevant risk factors for AMD such as fibrinogen, cholesterol, von Willebrand factor, and α2‐macroglobulin results in the reduction of blood and plasma viscosity as well as erythrocyte and thrombocyte aggregation. Pulses of lowering blood and plasma viscosity performed as a series of Rheopheresis treatments lead to rapid changes of blood flow, subsequently inducing sustained improvement of microcirculation and recovery of retinal function. Two controlled randomized clinical trials demonstrated the safety and efficacy of Rheopheresis for the treatment of AMD patients, especially for those with the dry form. Recently the interim analysis of the sham‐controlled, double blind, randomized multicenter Multicenter Investigation of Rheopheresis for AMD (MIRA‐I) trial confirmed these results. The framework of completed and still ongoing controlled clinical trials in combination with postcertification studies including the RheoNet registry represents a comprehensive quality management approach for this novel interdisciplinary therapy for AMD. The development and continuous update of guidelines for the precise indication of Rheopheresis for AMD follows the requirements of evidence‐based medicine.     

Apheresis in coronary heart disease with elevated Lp (a): a review of Lp (a) as a risk factor and its management

Lipoprotein (a) (Lp (a)) increases global cardiovascular risk, especially when LDL cholesterol is concomitantly elevated. Epidemiologic data show that Lp (a) concentration in plasma can be used to predict the risk of early atherogenesis in a dose-dependent manner and late stages of atherosclerosis are accelerated by elevated Lp (a). Therapeutic means to lower Lp (a) are limited. The most effective method to reduce plasma Lp (a) concentration significantly is therapeutic apheresis. Because apheresis is laborious and expensive, patients considered for this procedure should suffer from high Lp (a) concentrations, well beyond 50 mg/dL, and have manifested and progressive coronary heart disease despite maximal drug therapy. Experimental data and therapeutic results will be discussed in the present paper.     

Effects of immunoadsorption on the nt-BNP and nt-ANP plasma levels of patients suffering from dilated cardiomyopathy

Immunoadsorption (IA) represents an additional therapeutic approach in patients with severe heart failure due to dilated cardiomyopathy (DCM). nt-BNP and nt-ANP plasma levels are prognostic markers in patients with heart failure. The effect of IA on nt-BNP and nt-ANP plasma levels is unknown. In this case control study, 30 patients suffering from severe heart failure (LVEF < 35%) due to DCM were included. In 15 patients, IA was carried out in four courses of monthly intervals until month 3. For analysis of the acute and prolonged effects, the plasma levels of nt-BNP and nt-ANP were determined before and after each IA course. In 15 comparable DCM patients (controls), plasma levels of nt-BNP and nt-ANP were determined at baseline and after 3 months. LVEF remained stable during this study in the control group. In contrast, in the IA group after 3 months, LVEF increased from 29.7 +/- 1 to 38.6 +/- 2%, P < 0.001. In the control group, the nt-BNP and nt-ANP plasma levels remained stable during the 3 months of the study. In the IA group after the first IA course, the level of nt-BNP was acutely reduced from 1501 +/- 328 to 925 +/- 151 fmol/mL, P < 0.01. In addition, the nt-ANP level was reduced from 4439 +/- 1271 to 2897 +/- 825 fmol/mL, P < 0.01. In the IA group, the reduction of these two parameters remained detectable after 3 months before the last course: nt-BNP: 714 +/- 119 fmol/mL, nt-ANP: 2227 +/- 427 fmol/mL, P < 0.05. The improvement of left ventricular function during IA is accompanied by a reduction of nt-BNP and nt-ANP plasma levels in patients with DCM.     

Leukocyte Apheresis Using a Centrifugal Cell Separator in Refractory Ulcerative Colitis: A Multicenter Open Label Trial

Abstract: Recently, successful results of ulcerative colitis (UC) treatments with leukocyte apheresis have been reported by several institutes. To certify the efficacy of leukocyte apheresis in refractory UC patients, a multicenter open label trial was conducted, and results were analyzed. Fifty patients diagnosed with active steroid‐resistant UC were enrolled in this study from 14 medical centers. Using a centrifugal cell separator (Component Collection System, Haemonetics), leukocyte apheresis was performed once a week for 5 weeks. General conditions and abdominal symptoms were recorded daily, and laboratory tests were followed weekly. Changes of colonoscopic and histological manifestations of luminal activity through the study period were evaluated. At the end of the study period, stool frequency was decreased to less than 4 times a day in 68.4% (26 of 38) and serum C‐reactive protein (CRP) concentration was normalized in 56.7% (17 of 30) of the patients. Colonoscopic remission was achieved in 57.7% (26 of 45), and histological improvement was noted in 54.1% (20 of 37) of the patients tested. Improved disease activity was demonstrated in 74% (37 of 50) of the patients by general assessment criteria. Analysis of the trial data confirmed the valid clinical efficacy of leukocyte apheresis by centrifugal cell separator in refractory UC patients.