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Background In Austria, about 12 patients per 1 million inhabitants are treated currently with lipoprotein (LP-) apheresis. In 2016 it has been suggested, that about 5000 patients were treated worldwide with LP-apheresis, more than half of them in Germany. Regular LP-apheresis aims to decrease apolipoprotein B-rich lipoproteins and to reduce cardiovascular events. In this analysis we present the current situation of LP-apheresis in Austria and we evaluated the cardiovascular event rate 2 years before versus 2 years after starting LP-apheresis. Methods A retrospective analysis of 30 patients (19 men and 11 women) was performed at Athos Institute, Vienna, Austria. The study period included two years prior versus two years after the beginning of LP-apheresis. Cardiovascular events and interventions were defined as regarding the coronary (MACE) or the non-coronary (peripheral, cerebral or renal) vascular system. Results The first cardiovascular event before treatment initiation occurred at a mean age of 48.4 years (range 34–73), treatment was started at a mean age of 55.6 years (range 34–73). The mean rate of incidence of cardiovascular events per patient per 2 years before beginning of LP-apheresis (y-2 and y-1) versus 2 years during treatment (y+1 and y+2) was reduced by 77.78% (1.50 versus 0.33 events/patient/2 years, p = 0.003). Conclusions The significant reduction in MACE and vascular disease during regular LP-apheresis at weekly intervals is consistent with data from the literature. Difficulties arise in comparing such studies due to different definition of events or interventions and different study durations. However, LP-apheresis is an efficient treatment option and causes significantly prolonged event-free survival for patients at risk.

Background Lipoprotein(LP)-apheresis is the treatment of choice in patients suffering from severe familial hypercholesterolemia. A wide range of mechanisms has been claimed to be responsible for the known clinical benefit. Methods Patients suffering from heterozygous familial hypercholesterolemia undergoing LP-apheresis either with direct adsorption of lipoproteins (DALI) or dextran sulfate (DS) were examined. A total volume of 10 l blood was exchanged. Non-lipid effects, mainly concerning endothelial function (circulating endothelial cells, circulating endothelial progenitor cells, flow-mediated vasodilation, microalbuminuria) as well as left ventricular ejection fraction and homocysteine were assessed. Results A single LP-apheresis session improves paradox contractile response in statin intolerant patients, but not in those on regular statin therapy. In contrast, over a 6-months follow-up after treatment initiation, all the examined parameters (circulating endothelial cells, circulating endothelial progenitor cells, flow mediated vasodilatation, homocysteine, microalbuminuria and left ventricular ejection fraction) improved. When available, a comparison between DS vs. DALI was performed. In none of the subgroups a significant difference was noted. Discussion These findings indicate that beyond the well known lipid/lipoprotein lowering action the broad spectrum of functional tests examined reflecting mainly endothelial function is significantly improved by LP-apheresis treatment on the long-term and seems to be a key underlying reason for the clinical improvement seen in these patients.

Summary Autoantibodies play an important role in the pathophysiology of renal involvement in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), systemic vasculitis, and anti–glomerular basement membrane disease (or Goodpasture syndrome). Direct removal of autoantibodies therefore has been tried in various ways, first by plasma exchange. Today, immunoadsorption is the extracorporeal method that most effectively removes (pathogenic) immune complexes and antibodies. Although past data have shown efficacy and biocompatibility of immunoadsorption in (renal) SLE, it is still an experimental and expensive procedure, and evidence from randomized controlled trials is needed. Nevertheless, immunoadsorption is being used as a rescue therapy in life-threatening situations of SLE patients because of its fast mode of action and its acceptable safety profile. In granulomatosis with polyangiitis (GPA) (or Wegener’s granulomatosis), microscopic polyangiitis (MPA), and anti–glomerular basement membrane disease, the current standard is plasma exchange. Immunoadsorption, which probably would reduce the autoantibody burden more effectively, might be an even better more effective option, but sufficient evidence is lacking.

Left ventricular ejection fraction (LVEF) is a valuable measure to assess left ventricular systolic function. Lipid lowering therapy by statins has been shown to have an impact on LVEF already after a 6 months treatment. Higher doses of statins have been claimed to be more effective as compared to a conventional one and even a difference between lipophilic and hydrophilic compounds has been reported. The effect of regular lipoprotein-apheresis (LP-apheresis) on LVEF was previously poorly examined. Patients involved in a regular LP-apheresis program are supposed to undergo a number of follow-up investigations among them myocardial scintigraphy and LVEF, measured by radionuclide ventriculography.We examined 18 patients before initiation and after one year of ongoing LP-apheresis. 13 patients (11 males, 2 females, mean age 58.3 ± 5.3 years, groups A) were since more than a year on stable, unchanged statin treatment (atorvastatin 40 mg, simvastatin 40 mg, rosuvastatin 20 mg±ezetimibe), the other 5 patients (3 males, 2 females, mean age 57.1 ± 4.6 years, group B) were intolerant to statins being on micronized fenofibrate±resorption inhibitors (cholestyramine). All patients had a Lp(a) 30 mg/dl. As part of the usual follow-up monitoring, LVEF was determined by means of radionuclide ventriculography after application of 550 MBqThe follow-up LVEF was checked at a mean of 48.7 weeks in group A and 51.2 weeks in group B. Except in 1 patient (LVEF 46.8% before vs. 45.2% after LP-apheresis initiation) in group A we noted a significant increase in LVEF in 12 patients of group A (92%) and in all patients of group B. Mean LVEF increased significantly in both groups (A: 42.7±8.1 → 46.5±7.5% (p 0.001) and B: 41.9±8.4 → 46.5±6.3 %; p 0.001). The relative rise was nearly identical (group A 9.6%, in group B 9.7%).Our findings indicate that regular long-term LP-apheresis treatment apparently increases LVEF, independently on current statin treatment. This implies a role of lowering of atherogenic lipoproteins as underlying mechanism. A prospective study should clarify the relative extent of LVEF improvement induced by LP-apheresis.

Apheresis modalities including therapeutic plasma exchange and immunoadsorption enable the rapid removal of pathogenic components from circulation via an extracorporeal circuit. After separation of plasma from corpuscular blood components, the endogenous plasma is either replaced by a substitution fluid (therapeutic plasma exchange) or loaded in reusable adsorber columns, where immunoglobulins are adsorbed (immunoadsorption). Several indications for both apheresis modalities have been established, to date, especially in the treatment of various autoantibody-mediated diseases and in the peri-transplant setting.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. Conclusion: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

Manifestationen an der Haut und den hautnahen Schleimhauten werden bei etwa 80 % aller Patienten mit systemischem Lupus erythematodes (SLE) beobachtet. Welche weiteren Hautveranderungen konnen beim SLE zusatzlich zu den als SLE-Kriterien des American College of Rheumatism (ACR) klassifizierten (Schmetterlingserythem, chronisch kutaner Lupus erythematodes, Schleimhautulzera und erhohter Photosensitivitat) beobachtet werden? Es erfolgten eine ausfuhrliche Literaturrecherche in Peer-Reviewed-Journalen und eine Analyse der an unserer Abteilung verifizierten mukokutanen Manifestation von SLE-Patienten sowie eine Darstellung besonderer Krankheitsverlaufe. Berichtet wird uber die Vielfalt unspezifischer, aber fur den SLE typischen Hautveranderungen: periunguale Erytheme, periunguale Teleangiektasien und periunguale Splitterblutungen, Papeln an den Dorsalseiten der Finger und Hande, schuppende Erytheme, gelegentlich verbunden mit Nekrosen v. a. an den Ohren bei Komplementdefizienz und die bizarren Nekrosen des Antiphospholipidsyndroms. Anhand ausgewahlter Patienten demonstrieren wir ungewohnliche und seltene Krankheitsbilder, die mit einem SLE assoziiert auftreten konnen: die neutrophile urtikarielle Dermatose, den bullosen SLE und eine schwerwiegende Sepsis durch Neisseria flavescens bzw. Neisseria macacae. Aufgezeigt werden zahlreiche unspezifische Hautveranderungen, die typischerweise mit einem SLE-assoziiert sind, und komplexe, teils schwerwiegende Krankheitsbilder, die ausschlieslich beim SLE und anderen Immunfunktionsstorungen auftreten.

The prevalence of familial disorders of lipid metabolism in Europe is higher than believed so far. In severely affected patients in whom conventional combined lipid lowering agents are insufficient to achieve target values, patients being intolerant to all the available members of the statin family as well as in patients with elevated lipoprotein(a) (100 mg/dl) and progression of atherosclerotic vascular disease, despite even normal low-density lipoproteins (LDL)-cholesterol values, lipoprotein-apheresis treatment is indicated. The Austrian Apheresis Consensus compares the inclusion criteria for patients to be treated in Austria with those from Italy, Germany, Spain, Japan, UK and the United States. The cut off level of 100 mg/dl for lipoprotein(a) is higher in Austria as compared to the aforementioned countries (50 or 60 mg/dl, respectively). The available clinical data reveal that regular weekly lipoprotein apheresis not only results in a significant lowering of the respective atherogenic lipid and lipoprotein parameters, but also in a significant decrease in clinical events and interventions. The underlying mechanisms such as non-lipid effects, side effects as well as the different available treatment principles are compared. For patients meeting the inclusion criteria, lipoprotein apheresis is a safe and effective therapy significantly reducing vascular events.

The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody-incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry (ROTEM®) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM-146-peptide) and MF on levels of ABO antigen-specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P

Background. Recipient desensitization using blood group (BG)-specific immunoadsorption (ABO-IA) has proven to enable successful kidney transplantation across major ABO barriers. In this context, the efficiency of non-antigen-specific (semiselective) IA adsorbers has not yet been established. The objective of our study was to quantify anti-A/B antibody depletion by protein A-, peptide ligand- and anti-human immunoglobulin-based semiselective IA in comparison to ABO-IA. Methods. Eight ABO-IA-treated transplant candidates and 39 patients subjected to semiselective IA for a variety of different indications outside the context of ABO-incompatible transplantation were included. Antibody patterns (IgG, IgG1-4 subclasses, IgM, C4d-fixing reactivities) were analysed applying conventional agglutination testing and flow cytometry. Results. As assessed by sensitive flow cytometric antibody detection, ABO-IA-based desensitization led to a profound even though often incomplete reduction of anti-A/B reactivities. Persistent complement- or non-complement-fixing reactivities, however, were not associated with transplant rejection or capillary C4d deposition. Single sessions of semiselective IA turned out to be more effective than ABO-IA in decreasing levels of anti-A/B IgG [median reduction to 28 versus 59% (ABO-IA) of baseline values, P < 0.001). In contrast, BG-specific IgM (74 versus 30%, P < 0.001) and IgG3 (72 versus 42%, P < 0.05) were reduced to a lesser extent, without differences between tested adsorber types. Analysis of four consecutive IA sessions revealed that inferior efficiency could not be overcome by serial treatment. Conclusion. Our observation of limited adsorption capacities regarding distinct BG-specific Ig (sub)classes suggests caution in applying semiselective IA techniques in ABO-incompatible kidney transplantation

Background. Potent antibody depletion techniques have paved the way to successful ABO-incompatible transplantation. Considering its efficiency regarding IgG removal, the use of nonantigen-specifi cs emi-selective immunoadsorption (IA) has been advocated. One attractive strategy to overcome the caveat of incomplete IgM depletion and to interfere with complement activation could be the adjunctive use of membrane filtration (MF) to enhance the removal of macromolecules. Methods. To investigate the depletion efficiency of semiselective IA plus MF, we conducted a randomized, controlled, cross-over trial including patients on regular IA treatment for indications outside recipient desensitization. According to the results of sample size calculation, 14 subjects were enrolled. Two treatment sequences, a single session of IA plus MF followed by IA alone after ≥7 days (and vice versa), were analysed. Results. IA plus MF markedly enhanced the median per cent reduction of ABO-specific IgM determined by flow cytometry (primary end point; 59 versus 23%, P < 0.001) and haemagglutination (2 versus 1 titre steps, P < 0.001), respectively. Combined treatment also substantially lowered C1q concentrations (86 versus 58% reduction, P < 0.001) and the functionality of classical complement as reflected by impaired in vitro C3 activation capability. IgG was strongly reduced without any additional effect of MF. Conclusions. We demonstrate that the innovative strategy of combining MF with semi-selective IA may substantially increase IgM elimination and affect classical complement activation. Our findings suggest that this new treatment concept could be an efficient strategy for recipient desensitization in ABO- and HLA-incompatible transplantation.

Plasma lipoproteins such as LDL (low-density lipoprotein) are important therapeutic targets as they play a crucial role in macrophage biology and metabolic disorders. The impact of lipoprotein profiles on host defense pathways against Gram-positive bacteria is poorly understood. In this report, we discovered that human serum lipoproteins bind to lipoteichoic acid (LTA) from Staphylococcus aureus and thereby alter the immune response to these bacteria. Size-exclusion chromatography and solid-phase-binding analysis of serum revealed the direct interaction of LTA with apolipoproteins (Apo) B100, ApoA1, and ApoA2. Only ApoB100 and the corresponding LDL exerted biological effects as this binding significantly inhibited LTA-induced cytokine releases from human and murine immune cells. Serum from hypercholesterolemic mice or humans significantly diminished cytokine induction in response to S. aureus or its LTA. Sera taken from the patients with familial hypercholesterolemia before and after ApoB100-directed immuno-apheresis confirmed that ApoB100 inhibited LTA-induced inflammation in humans. In addition, mice in which LDL secretion was pharmacologically inhibited, displayed significantly increased serum cytokine levels upon infection with S. aureus in vivo. The present study identifies ApoB100 as an important suppressor of innate immune activation in response to S. aureus and its LTA.

Background. Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available. Methods. IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 6 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (antidsDNA) levels (secondary outcomes). Full/partial remission was defined as � 0.5/� 1.0 g/day for proteinuria, � 5/ � 8 for SLEDAI and � 25/� 50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events. Results. Short-term IAS (� 1 year) resulted in a significant reduction of proteinuria (9.2 6 3.7 to 2.3 6 2.4, P ¼ 0.0001), disease activity (SLEDAI 19 6 8t o 46 2, P ¼ 0.0004) and dsDNA levels (168 6 205 to 45 6 34, P ¼ 0.001). In patients without remission after 1 year (n ¼ 5), prolonged IAS decreased proteinuria from 4.3 6 2.4 to 0.5 6 0.4 g/day, P ¼ 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 6 0.30) and infections (0.66 6 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed. Conclusion. IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of observation.

ABO-incompatible kidney transplantation is a promising strategy for enlargement of living-donor pools. In recent years, recipient desensitization by blood group antigen-specific immunoadsorption, together with rituximab and intravenous immunoglobulin, has allowed excellent graft performance after ABO-incompatible transplantation. Adopting this protocol, originally described by Tyden and coworkers, we performed four living-donor renal transplants across the ABO barrier (A1-->0, A1-->B, B-->A1, A2-->0) between July 2007 and August 2008. Recipients were aged 25-66 years, donors 49-69 years. A protocol of on-demand immunoadsorption was followed, based on serial post-transplant antibody monitoring. Substantial and sustained decrease of blood group antibody levels was achieved in all four recipients, therefore post-transplant immunoadsorption was not needed. Graft and patient survival after 4-18 months' follow-up was 100%. Current serum creatinine was 1.3-2.0 mg/dl. Two grafts showed C4d deposits in peritubular capillaries in the complete absence of typical morphological features of antibody-mediated rejection. One recipient experienced early graft dysfunction, diagnosed as Banff borderline lesion, which responded well to steroid pulse therapy. The same recipient developed de novo interstitial fibrosis/tubular atrophy and arteriolar hyalinosis, presumably the result of suboptimal control of blood pressure and/or calcineurin inhibitor therapy. Two of the four recipients developed lymphoceles necessitating surgical revision. Apart from urinary tract infection in three patients and subclinical CMV in one, no major infectious complications were reported. Notably, two stable recipients developed polyoma BK viremia without clinical or morphological manifestations of polyomavirus-associated nephropathy. The results obtained in our small series support the earlier reported high efficiency of desensitization based on antigen-specific immunoadsorption. Nevertheless, the lack of long-term data will necessitate continuous and prudent consideration of the benefits and risks of this strategy.

Using standard real time sonography, renal cortical echogenicity, renal length, intrarenal cystic structures and renal calculi were evaluated in 63 patients (30 men, 33 women) in end-stage renal parenchymal diseases (glomerulonephritis n = 21, diabetic glomerulosclerosis n = 9, analgesic nephropathy n = 14, chronic atrophic pyelonephritis n = 19). Patients with glomerulonephritis and diabetic glomerulosclerosis presented with larger kidneys and only slightly increased cortical echogenicity as compared to analgesic nephropathy and chronic atrophic pyelonephritis. In addition, intrarenal cystic structures were found in 50% of the patients with analgesic nephropathy and in 31% of the patients with pyelonephritis, compared with only 14% and 11% in patients with glomerulonephritis and diabetic glomerulosclerosis, respectively. Intrarenal calcifications were more frequent in pyelonephritis and analgesic nephropathy. In end-stage renal parenchymal disease, sonography might be able to distinguish between different types of renal medical disorders.

A novel highly selective single-use IgE-immunoadsorber, IgEnio, has been developed using BM10, a non-anaphylactic fragment of a monoclonal anti-human IgE antibody. In a proof of concept study, IgEnio was used to deplete IgE from the plasma of patients suffering from allergic asthma. In a randomized open-label trial (NCT02096237) 15 highly allergic asthmatics with a total IgE of ≥300U/ml were included. Ten patients were randomly allocated to the treatment group, 5 to a control group. During 16 weeks, every treated patient had a total of 9 IgE-adsorptions: 3 in the 1 st , the 6 th and the 11 th week, respectively. Control visits were scheduled between the weeks of treatment and at the end of the study. Aims of the trial were (1) reduction of total IgE by ≥50% after the last treatment as compared to the beginning of the trial and (2) to demonstrate safety of the new IgE-adsorber. In addition, lung parameters and symptoms were recorded to trace clinical effects. All study participants completed the trial but one, who dropped out for personal reasons before first treatment. Irrespective of individual total-IgE levels (range 308-2518U/ml) IgE was reduced by 79% on average per treatment and by 86.2% (±5.1%) over the entire treatment period. Most adverse events possibly related to the investigational treatment concerned deviations of laboratory parameters and allergic reactions of the skin which are also observed in other immunoadsorption therapies. However, all adverse events were effectively medicated and IgE-adsorptions could be completed in all patients. Using IgEnio, a reliable and safe reduction of total-IgE was achieved, even for extremely elevated IgE-levels. Further studies will focus on clinical efficacy of IgE-adsorption.

The emergence of anticardiolipin antibodies in patients with systemic lupus erythematosus is a serious occurrence in regard to a high risk for thrombosis and thromboembolic complications, fetal loss, and renal insufficiency. In an observational analysis, we studied anticardiolipin antibodies during immunoadsorption therapy.We analyzed the magnitude and time course of serum concentrations of the immunoglobulin G (IgG) and IgM subtypes of anticardiolipin antibodies (CIgG and CIgM) along with IgG and IgM, antinuclear antibodies, and antibodies to double-stranded DNA before and after single immunoadsorption sessions and their long-term course in 11 patients with systemic lupus erythematosus.Single immunoadsorption sessions (n = 842) led to a rapid decline in CIgG and CIgM levels by 62.94% +/- 21.60% and 42.02% +/- 22.14%, respectively (P0.0001), along with a corresponding decline in serum levels of antinuclear antibodies (65.04% +/- 18.83%), antibodies to double-stranded DNA (64.67% +/- 21.20%), IgG (58.11% +/- 16.84%), and IgM (32.15% +/- 15.58%). Reduction rates of CIgG and CIgM levels were greater when high initial concentrations (P0.0001) and low IgG levels (P0.0001) were present. Mean reductions in pretreatment values of CIgG and CIgM during 6 months of immunoadsorption therapy were 42.85% +/- 39.94% and 29.39% +/- 70.41% (mean number of sessions/patient = 21.55) and for the 1-year period were 63.20% +/- 22.49% and 58.05% +/- 40.16% (mean number of sessions/patient = 30.46).We observed that immunoadsorption therapy is an effective method to reduce anticardiolipin antibody levels rapidly and keep them at a low level in the long term.

BACKGROUND Kidney transplant recipients with a current positive complement-dependent cytotoxicity crossmatch (CDCXM) are at high risk for hyperacute rejection and graft loss. Immunoadsorption (IA) represents an efficient strategy to remove donor-specific alloantibodies. In this analysis, we evaluated effectiveness of peritransplant IA as an anti-humoral strategy to overcome a current positive CDCXM in presensitized renal allograft recipients. METHODS Between 1999 and 2003, 40 high risk cadaveric kidney allograft recipients (median CDC panel reactive antibody [PRA] level, 77%; number of retransplants, n = 38) were subjected to peritransplant IA with protein A (one pretransplant IA session followed by a course of repeat posttransplant IA sessions) in addition to preemptive antilymphocyte antibody therapy. RESULTS In nine of these patients, a current positive CDCXM was rendered negative by a single pretransplant IA session. Thirty-one recipients had a negative CDCXM already before pretransplant IA. No difference in graft survival was found between CDCXM-positive and CDCXM-negative recipients (3-year graft survival, 78% vs. 71%, P = 0.6). Comparable rates of immunological graft loss at 3 years were observed (11% vs. 13%, P = 0.8). Patient groups did not significantly differ with respect to median serum creatinine at 1 year (1.23 mg/dL [CDCXM-positive] vs. 1.57 mg/dl [CDCXM-negative], P = 0.07) and at the end of follow-up (median 32 months; 1.19 mg/dL vs. 1.63 mg/dL, P = 0.06). Moreover, patient groups showed similar rates of biopsy-proven cellular rejection (11% vs. 20%) or C4d-positive graft dysfunction (33% vs. 32%). CONCLUSION Our results demonstrate that peritransplant IA enables successful cadaveric kidney transplantation in the context of a positive CDCXM.

OBJECTIVE: In systemic lupus erythematosus (SLE), extracorporeal procedures aiming at reduction of immunoglobulin (Ig) and immune complexes (IC) are used as a rescue therapy. Plasma exchange (PE) has not been proven overall effective in SLE, and long-term treatment in particular has been associated with severe bacterial and viral infections. Immunoadsorption (IAS), in contrast, selectively removes Ig and IC and may thus be safer. We therefore investigated the rate of infections in SLE patients who were undergoing long-term IAS. METHODS: 16 SLE patients were treated with ≥10 courses of IAS, and nine patients with highly active disease received pulse cyclophosphamide (IVCP) therapy in parallel. We retrospectively analysed the records of all these patients for the occurrence of infections. Patients receiving IAS therapy plus IVCP were compared with 25 patients with similarly active disease treated with standard IVCP therapy within the same observation period. Patients receiving IAS without additional IVCP were compared with patients with similarly moderate disease activity receiving neither IAS nor IVCP. RESULTS: No potentially life-threatening viral infection occurred in IAS-treated patients and episodes of herpes zoster were equally distributed. No severe infection was observed during IAS without concomitant cyclophosphamide. As expected, more patients with highly active disease receiving IVCP experienced infections than those with less active disease (16 of 34 [47%] vs. 2 of 22 [9%], p < 0.04). On comparing the two groups with highly active disease, infections were similar (IAS plus IVCP, 3 of 9 patients [33%]; IVCP only, 5 of 25 [20%]), but one patient receiving IAS plus IVCP died of septicaemia. Disease activity significantly decreased in both groups treated with IAS. CONCLUSION: IAS has an acceptable safety profile with regard to severe infections and appears safe with regard to severe viral disease. Highly active disease and IVCP therapy increase the risk of severe infections in SLE.

Dose-dependent effect of parenteral iron therapy on bleomycin-detectable iron in immune apheresis patients. Background Iron deficiency and anemia are commonly encountered in patients with autoimmune diseases undergoing immune apheresis. This makes erythropoietin and iron substitution necessary in most patients. However, intravenous iron therapy may result in an increase of potentially toxic nontransferrin-bound iron. Methods We examined the effect of 50 mg or 100 mg of iron (III) sucrose on bleomycin-detectable iron (BDI) in immune apheresis patients. Six patients with autoimmune disorders and normal kidney function were enrolled. Before and after the injection of 50 mg or 100 mg of iron (III) sucrose, BDI was measured in serum samples at five different time points. Results There was no BDI traceable before injection of iron (III) sucrose. BDI was present in serum of all patients after the administration of 100 mg of iron (III) sucrose in concentrations up to 0.49 μmol/L. In contrast, only one patient showed BDI at a concentration of 0.16 μmol/L after the administration of 50 mg of iron (III) sucrose. Conclusion We conclude that if parenteral iron is administered after apheresis treatment, despite the equal tolerability, use of 50 mg of iron (III) sucrose is superior to 100 mg of iron (III) sucrose in avoiding the formation of potentially toxic nontransferrin-bound iron.

Background. Immunoadsorption is increasingly used to treat antibody-mediated autoimmune diseases. To prevent microbial growth during storage, reusable protein A–Sepharose gel columns are primed with ethyl mercury thiosalicylate (thiomersal, 0.1% solution) and rinsed with phosphate buffer before use. In this study, we tested the hypothesis of systemic mercury exposure in protein A immunoadsorption. Methods. Whole blood mercury levels were measured by atomic absorption spectroscopy before and after protein A immunoadsorption (11 patients, 26 treatments), anti-IgG immunoadsorption (eight patients, 13 treatments) and LDL apheresis (DALI and Therasorb systems; nine patients, 14 treatments). Results. Patients treated with protein A immunoadsorption had significantly elevated baseline mercury levels compared with the other groups, which were not different from healthy controls. Following protein A immunoadsorption, mercury levels increased from 5.9±1.4mg/l (mean±SEM, normal

Background. Major ABO-incompatibility can be associated with haemolysis, prolonged red cell aplasia (PRCA) and higher peri-transplant mortality resulting from organ toxicity after conventional and nonmyeloablative allogeneic haematopoietic stem cell transplantation. Different therapeutic strategies have been developed to allow erythroid reconstitution in these patients. Methods. We present three patients, who developed PRCA after non-myeloablative allogeneic haematological stem cell transplantation for haematological malignancies. The patients were treated with IgTherasorb immunoadsorption (five treatments per week) to remove persisting incompatible isohaemagglutinins. Results. Two patients became transfusion independent after 12 and 14 treatments. In one patient, however, no reduction of the isohaemagglutinin titres could be observed after 25 treatments, probably due to persistence of his underlying disease. Conclusions. Although Ig-Therasorb immunoadsorption was effective in only two patients, it seems to be a promising therapeutic option for patients with PRCA after allogeneic non-myeloablative haematological stem cell transplantation.

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Summary Background: Pemphigoid (herpes) gestationis is a rare blistering disease of pregnancy. Topical and systemic corticosteroids and antihistamines are usually sufficient for treatment. Case report: A patient suffering from severe, therapy-resistant pemphigoid gestationis was successfully treated with the additional use of six sessions of immunoapheresis. Systemic corticosteroids could be tapered and serum autoantibody levels to bullous pemphigoid antigen 2 (BPAG2 = BP180) significantly dropped during this treatment. Conclusion: Immunoapheresis represents a helpful therapeutic option with few side effects for severe cases of pemphigoid gestationis, unresponsive to conventional treatment. Zusammenfassung Hintergrund: Pemphigoid (Herpes) gestationis ist eine seltene, blasenbildende Schwangerschaftsdermatose. Topische und systemische Kortikosteroide und Antihistaminika sind im Normalfall zur Therapie ausreichend. Fallbericht: Eine Patientin litt unter einer schweren, therapieresistenten Form eines Pemphigoid gestationis. Unter einer Zusatztherapie mit 6maliger Immunapherese heilten die Hautlasionen vollig ab und orales Kortison konnte ausgeschlichen werden. Die Titer der Autoantikorper gegen das bullose Pemphigoid Antigen 2 (BPAG2 = BP 180) fielen unter dieser Therapie deutlich ab. Schlusfolgerung: Immunapherese ist eine rationale, nebenwirkungsarme Therapieoption in Fallen von schwerem, therapieresistenten Pemphigoid gestationis.

To further reduce low-density lipoprotein-cholesterol (LDL-C), atorvastatin treatment was investigated in patients with homozygous (n = 4) and heterozygous (n = 10) familial hypercholesterolemia (FH) undergoing LDL-apheresis. After a wash-out period of 4 weeks, atorvastatin therapy was administered in escalating doses (10 up to 80 mg/d). LDL-apheresis was performed at weekly intervals during the entire study period. The LDL-C concentration decreased from 240 [plusmn] 35 mg/dL after the wash-out period to 206 [plusmn] 63 mg/dL during treatment with 10 mg atorvastatin. Four weeks of treatment with 80 mg atorvastatin resulted in an additional 24% ( P [lt ] .05) reduction in LDL-C. LDL-C increased from 28.8 [plusmn] 14.2 mg/dL immediately after apheresis to 156.6 [plusmn] 25.5 mg/dL at day 7. LDL-C values remained below the recommended target range for an extended duration of 48 hours in atorvastatin-treated patients, but not in those without concomitant lipid-lowering drug therapy. The levels of high-density lipoprotein-cholesterol (HDL-C) and plasma fibrinogen were unchanged during the entire study period. No adverse events were observed with atorvastatin treatment. Finally, high-dose atorvastatin therapy resulted in a 40% reduction in LDL-apheresis sessions in these patients. Our results show that LDL-C reduction by atorvastatin is a safe and effective therapy in LDL-apheresis patients with severe heterozygous or homozygous FH.

Background. Re-transplanted kidney allograft recipients with high levels of panel reactive antibodies (PRA) are at increased risk of early immunologic graft loss. In these patients, prophylactic peri-operative antibody depletion by immunoadsorption (IA) could prevent humoral graft injury and thus, in combination with anti-cellular rejection therapy, improve graft survival. Methods. Twenty re-transplanted and broadly immunized cadaver kidney recipients (median PRA reactivity 87%, range 55–100%) were treated with IA (protein A) immediately before transplantation and during the early post-transplantation period (median number of IA sessions 11, range 1–24). Patients received additional prophylactic anti-lymphocyte antibody therapy. Nineteen patients had a negative pre-transplant crossmatch. In one patient, a positive cross-match was rendered negative by the pre-transplant IA session. Results. One-year graft survival was 80% and patient survival 95%. Median (range) serum creatinine in functioning grafts was 1.6 (0.8–2.7) mgudl at discharge and 1.5 (1.0–5.8) mgudl at 1 year. Two grafts were lost due to acute vascular rejection, whereby one rejection occurred after withdrawal of immunosuppression due to septicaemia. One patient had acute cellular rejection, which was reversed by a second course of anti-lymphocyte antibody therapy. Thrombotic microangiopathy and surgical complications were the causes for one graft loss each. Retrospective immunohistochemistry revealed peritubular C4d staining, a presumed marker for humoral alloreactivity, in 12 out of 15 biopsies. Conclusions. These results suggest that prophylactic peri-operative IA and anti-lymphocyte antibody therapy might be an effective therapeutic strategy for the prevention of early graft failure in sensitized re-transplant recipients.

For patients with severe forms of autoimmunity, including systemic lupus erythematosus (SLE), purging autoreactive T cells from the immune repertoire by transplanting autologous hematopoietic stem cells (ASCT) is a therapeutic option. We describe an 18-year-old woman with SLE who had been treated with corticosteroids, azathioprine, cyclophosphamide (CYC), and immunopheresis for 4 years, during which time mechanical ventilation for lupus pneumonitis had been repeatedly required. After the patient was conditioned by administration of CYC and antithymocyte globulin, a total of 8.87 × 106 purified CD34+ cells per kg of body weight was infused. Hematopoietic regeneration was observed within 9 days. Twenty-one months after ASCT, the patient continues to be in complete clinical remission, with no signs of SLE-related disease activity and without any immunosuppressive medications. Her pulmonary function has returned to normal. Although a longer followup is required for assessment of the durability of response, the patient's course indicates that ASCT may be a way to reinduce tolerance in patients with SLE.

Acute treatment of myasthenic crisis with immunoadsorption (IA) or plasma exchange is well established. The efficiency of chronic apheresis therapy in myasthenia gravis (MG), however, and its efficacy in reducing concomitant potentially harmful immunosuppressive therapy, is unknown. We treated 13 patients with therapy-resistant MG or severe steroid or azathioprine therapy-related side effects, or both, with long-term IA [median, 38 (range: 16–59) months]. IA was performed every second day until partial remission was achieved (modified Osserman score

The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody-incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry (ROTEM®) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM-146-peptide) and MF on levels of ABO antigen-specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P0.001), whereby four patients showed post-treatment fibrinogen concentrations below 100 mg dL(-1). In support of a critical contribution of fibrinogen depletion to impaired coagulation, extrinsically activated ROTEM(®) analysis revealed a marked reduction in fibrinogen-dependent clot formation upon IA+MF (59% median decrease in FIBTEM mean clot firmness (MCF) as compared to 24% after IA alone, P0.001). Moreover, the addition of MF led to a substantial prolongation of activated partial thromboplastin time, possibly due to depletion of macromolecular coagulation factors contributing to intrinsically activated coagulation. Our study demonstrates substantial effects of combined IA+MF on clot formation, which may be mainly attributable to fibrinogen depletion. We suggest that the use of combined apheresis in the setting of transplant surgery may necessitate a careful monitoring of coagulation.

Background: Immunoadsorption (IAS) and therapeutic plasma exchange (TPE) are considered safe although fibrinogen is removed. To date no comparison of fibrinogen reduction and associated risk of bleeding in apheresis exists. Methods: Retrospective analysis of TPE, three IAS adsorbers, and combined TPE/IAS regarding fibrinogen reduction and bleeding incidence in 67 patients (1,032 treatments). Results: TPE and TPE/IAS reduced fibrinogen by 64 ± 11% and 58 ± 9%, leading to concentrations Conclusion: Hypofibrinogenemia occurs in 20% of patients after TPE and TPE/IAS, but rarely after IAS. IAS removes fibrinogen independently of volume processed. Overall, bleeding is rare in apheresis.

To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P

Background Calcification of the coronary vessel wall is regarded as a marker of advanced coronary atherosclerosis. Methods To test whether patients with heterozygous familial hypercholesterolemia (FH) exhibit excessive calcification of the coronary vessel wall, we quantified coronary artery calcium in LDL-apheresis treated FH-patients with known severe coronary artery disease (CAD) (n = 10), in patients with moderate hypercholesterolemia and known severe CAD (n = 10), and in asymptomatic controls (n = 10) using electronic beam CT. The total coronary calcium score (Agatston-Score), the number of calcified lesions and the calcified plaque volume were evaluated for this study. Results CAD-patients with FH, although on average 10 years younger, had a significantly higher total coronary calcium score (702/2018/2890), number of lesions (34/43/49) and calcified plaque volume (700/1818/2313) compared to patients with CAD only (480/641/1362, 10/16.5/22, 480/588/1209, respectively) and controls (10/47/137, 2/4/10, 15/50/144, respectively). Furthermore, we observed a significant correlation (r = 0.93; P < 0.01) between LDL- cholesterol levels (pretreatment levels of the CAD-FM group) and the total coronary calcium score in all three groups. Our results demonstrate that coronary artery calcification is more extensive in CAD-patients with FH than in CAD-patients with moderate hypercholesterolemia. In addition, we provide evidence that the amount of calcium in the coronary vessel wall in FM patients result from a long lasting history of elevated LDL-Cholesterol levels. Conclusion These findings emphasize the significance of LDL-cholesterol as a risk factor for atherosclerosis and underline the importance of early diagnosis of CAD and early cholesterol lowering therapy in FH patients.

Coagulation inhibitors may occur as alloantibodies in patients with congenital factor deficiencies or as autoantibodies in patients with a previously normal coagulation. We treated 10 patients with factor VIII inhibitors (three haemophiliacs and seven patients with acquired factor VIII inhibitors) and one patient with a factor V inhibitor using extracorporeal immunoadsorption to immobilized antibodies against human immunoglobulins (Ig-Therasorb). The initial inhibitor titre was between 18 BU/ml and 540 BU/ml. Nine patients had signs of bleeding. Eighty-nine immunoadsorption sessions were performed in the 11 patients (8.1 +/- 5.1 per patient), each processing 6980 +/- 880 ml of plasma in 3.8 +/- 0.5 h. The mean reduction of the inhibitor titre was 71.9 +/- 19.4% per session. Serum IgG, IgA and IgM levels decreased by 68.7 +/- 10.1%, 55.7 +/- 12.7% and 48.6 +/- 11.1% respectively. In two haemophiliac patients, an initial titre reduction prior to an immune tolerance protocol was performed. Another haemophiliac patient was treated because of acute cerebral bleeding. In six out of eight patients with acquired inhibitors, a durable elimination was achieved within a median of 18 d. Treatment was safe and well-tolerated and seems to be a promising method in the treatment of patients with coagulation inhibitors, especially when a fast inhibitor titre reduction is necessary.

Patients with Goodpasture's syndrome presenting with dialysis-dependent end-stage renal failure at diagnosis almost never regain independent renal function. We report a patient with a 100% crescentic lesion in whom reversal of dialysis dependence was achieved by immunoadsorption together with immunosuppression. In a second patient, early initiation of immunoadsorption was able to completely restore normal renal function as early as 1 month after the start of treatment. These data give evidence of the use of immunoadsorption as a hopeful alternative to conventional plasma exchange in patients with Goodpasture's syndrome showing advanced renal failure.

Various LDL-apheresis systems have gained wider clinical acceptance in recent years to treat patients with severe familial hypercholesterolaemia, in particular in patients with coronary artery disease. For each single device data on efficacy have been provided, but up to now no comparative analysis including the novel direct adsorption of lipoproteins from whole blood has been reported. This prospectively designed cross-over comparison of three commercially available LDL-apheresis systems (immunoadsorption, IMAL; dextran sulphate adsorption, DSA; direct adsorption of lipoproteins, DALI) was performed in eight patients with homozygous (n = 3) and heterozygous (n = 5) familial hypercholesterolaemia. Removal of atherogenic lipoproteins was highly effective in all systems, for LDL-cholesterol in particular: DSA: - 84.3 +/- 6.2%; IMAL: -82.1 +/- 8.3%; DALI: -76.6 +/- 7.2% (P < 0.05 as compared DALI versus IMAL and DSA). A reduction in Lp(a) of about 63% was achieved by each device. Loss in HDL-cholesterol was highest with IMAL (-21.3 +/- 4.9%, P < 0.05) as compared to the other two treatment modalities. DSA decreased HDL-cholesterol by - 10.4 +/- 6.1% and the DALI system by -12.7 +/- 5.0%. Remarkable differences were found for the removal of fibrinogen (DSA: -29.8 +/- 14.7%, (P < 0.05 versus DALI/IMAL); IMAL: -21.4 +/- 10.1% (P < 0.05 versus DALI); DALI: -14.8 +/- 8.0%). The shortest duration for treatment was achieved by the DALI system (135 +/- 20 min, P < 0.05 versus IMAL (195 +/- 20 min) and DSA (187 +/- 29 min)). No side effects were recorded in the total of 96 treatments performed during the study. Long-term observations have yet to prove whether these differences in efficacy may be of clinical relevance.

Extracorporeal elimination of low density lipoprotein (LDL) is frequently used in drug-resistant hypercholesterolemia. LDL-immunoapheresis selectively removes LDL and lipoprotein(a) [Lp(a)] from plasma. Lipid peroxidation is one unwanted side effect, that occurs during extracorporeal plasma treatment. The purpose of this study was to investigate the effect of LDL immunoapheresis on lipid peroxidation. Before and after a single LDL-immunoapheresis treatment, plasma concentrations of lipid hydroperoxides, determined with two different spectophotometric assays, thiobarbituric acid-reacting substances (TBARS), determined spectrophotometrically and malondialdehyde (MDA), determined by an MDA-TBA/HPLC method, were measured in 13 hypercholesterolemic patients. In addition MDA was also determined in the eluate of the apheresis column. Before treatment, plasma cholesterol and LDL cholesterol concentrations were significantly higher in patients than in healthy control subjects, as were the lipid peroxidation products. LDL-immunoapheresis treatment of the patients led to significant decreases in total cholesterol (69+/-8%), LDL-cholesterol (79+/-7%), HDL-cholesterol (35+/-17%), triglycerides (38+/-21%), apolipoprotein-B (77+/-6%), apolipoprotein-A1 (25+/-5%) and Lp(a) concentrations (76+/-10%). Changes in plasma lipid peroxide concentrations (17+/-8 nmol/l before vs. 14+/-5 nmol/l after treatment) were not significant, neither were those in TBARS (3. 0+/-2.6 micromol/l vs. 2.3+/-1.3 micromol/l) or MDA concentrations (1.03+/-0.17 micromol/l vs. 1.0+/-0.20 micromol/l). Patients with high baseline values showed a decrease, whereas others did not. MDA was present (0.57+/-0.13 micromol/l) in the eluate of the apheresis column, suggesting that, along with LDL, lipid peroxidation products are also removed. From these results we conclude that a single LDL-immunoapheresis treatment effectively reduces LDL and Lp(a) in the absence of increases in plasma lipid peroxidation products.

This article reviews the relevance of immunoadsorption in the treatment of haemophilic patients with inhibitors.Immunosorba (sepharose-bound staphylococcal protein A) and Ig-Therasorb (sepharose-bound polyclonal sheep antibodies to human immunoglobulin) columns are suitable for the clinical use of immunoadsorption. They allow the processing of large plasma volumes (7,000 ml) without relevant side-effects.A haemophilic patient was treated with the Malmö protocol, another was admitted with intracerebral bleeding. Immunoadsorption reduced the inhibitor titer by 70-90%.Immunoadsorption can be used in cases of acute bleeding, before surgery, acquired factor VIII (FVIII) antibodies, and before the start of immune tolerance therapy. We suggest the inclusion of this method in immune tolerance protocols in order to improve levels, recovery, and half-life of FVIII and to save concentrates.

This study was performed to investigate the effect of low-density lipoprotein (LDL) immunoapheresis on lipoprotein(a) [Lp(a)] reduction in patients with heterozygous and homozygous familial hyperlipidemia (N=16) and insufficient response to lipid-lowering agents. By desorption of approximately 5,700+/-500 mL of plasma, a mean reduction in total cholesterol of 62% (P < .001) and in LDL-cholesterol of 70% (P < .001) was achieved. Lp(a), which was elevated at study entry in seven of these patients (82.1+/-34.3 mg/dL; range, 48 to 148 mg/dL), was reduced during the initial LDL-apheresis procedure by 74.8%+/-14.1% (P < .001). Long-term apheresis treatment performed at weekly intervals resulted in an mean reduction in Lp(a) pretreatment values to 39.1+/-28.5 mg/dL (-54%; P < .001). Desorbed Lp(a) was measured at the waste of the columns for 31 apheresis treatments. Lp(a) concentration of the column waste was higher in patients with elevated serum Lp(a) pretreatment values as compared with those with Lp(a) serum values within the normal range (elevated Lp(a), 1,420+/-380 mg; without elevated Lp(a), 235+/-190 mg; P < .001). The rate of return of Lp(a) following apheresis treatment scheduled at weekly intervals was comparable to that of LDL-cholesterol.