The Role of Immunoadsorption in Clinical Nephrology
Norbert Braun and Teut Risler
Sektion Nieren- und Hochdruckkrankheiten of the Universitätsklinikum
Tübingen, Germany
Corresponding Author's Address
Dr. Norbert Braun, MD
Sektion Nieren- und Hochdruckkrankheiten
Universitätsklinikum
Leiter: Prof. Dr. T. Risler, MD
Otfried-Müller-Str. 10
72076 Tübingen
Germany
Tel.: ++49 7071 2983172
Fax: ++49 7071 293174
Email: nbraun@uni-tuebingen.de
General Considerations Extracorporeal immunoadsorption is known for about twenty years but has only recently attracted attention by the physicians because plasmapheresis failed to prove its effectiveness in many autoimmune diseases. Thus, research focused on other tools for the elimination of pathogenic antibodies and circulating immune complexes. This article summarises the results of clinical investigations in this field focusing on immunoadsorption in certain autoimmune and renal diseases.
Immunoadsorption is capable to eliminate huge amounts of immunoglobulins from the patient's circulation with a minimum of side effects known for plasmapheresis. In contrast, conventional plasma exchange removes antibodies and other plasmatic factors to about 50 – 75% [1]. It has to be emphasised that immunoglobulins are distributed in the intravascular and extravascular compartments in approximately equal amounts. Inflammatory processes often occur in the tissue and not in the vascular bed. Simple removal of immunoglobulins from the circulation does not necessarily result in stopping the immune process. Repeated treatment cycles with adequately processed plasma volumes must be used to overcome redistribution of pathological autoantibodies. Concomitant administration of intravenous immunoglobulins seems to attenuate the effect of immunoglobulin adsorption in certain circumstances, like systemic lupus erythematosus, although both treatments have been shown to be effective when used alone [2]. It has to be stressed that extensive immunoadsorption is mandatory to achieve an effect on the humoral immune system superior to that achieved by plasmapheresis [3]. Nevertheless, the almost complete elimination of IgG results in a severe humoral immune deficiency and clinicians must be aware of any infectious complication while classical immunological screening may fail.
Unfortunately, almost no controlled trials for the application of immunoadsorption have been published yet. Most of the knowledge about immunoadsorption is based on uncontrolled case series and individual observations. Therefore, indications for extracorporeal immunoadsorption are presently limited to HLA-pre-sensitised kidney recipients, rapidly progressive glomerulonephritis type I, chemotherapy associated haemolytic uraemic syndrome, life-threatening autoimmune diseases, and to clinical situations of autoimmune diseases where cytotoxic treatment is contraindicated [4]. In most other cases there seems to be no advantage over immunosuppression alone because immunoadsorption does not cure the disease and whenever remission could be achieved it has to be maintained by conventional means. Up to now, it is not known whether the combination of immunoadsorption with immunosuppression could result in a lower dose of applied cytotoxic drugs.
Immunoadsorption devices can be subdivided into non-selective, semi-selective
and highly selective adsorbers. While non-selective adsorbers (dextran-sulphate,
tryptophan
and phenylalanine) reduce the plasma levels of many
different substances like fibrinogen, albumin, lipids and immunoglobulins,
semi-selective adsorbers (staphylococcal
protein A, anti-human Ig Adsorber)
show affinity to only one group of plasma proteins. Highly-selective
adsorbers eliminate specific substances without changing the blood
levels of other plasma components. Technically, there are single-use and
re-usable adsorbers available.
Table 1: Currently available adsorber devices for autoimmune diseases
in Europe.
| Selesorb | IM-TR 350, IM-PH 350 | Prosorba | Immunosorba | Ig-Therasorb | Miro | |
| Company | Kaneka, Wiesbaden, Germany | Asahi-Medical, Japan (DIAMED, Köln) | Fresenius, St. Wendel, Germany | Fresenius, St. Wendel, Germany | Plasmaselect, Teterow, Germany | Fresenius, St. Wendel, Germany |
| Adsorber | Dextran-sulphate | Tryptophan, Phenylalanin | Protein A | Protein A | Polyclonal sheep anti-human Ig | C1q-Ligand |
| Matrix | Polyvinylalcohol | Silica | Sepharose | Sepharose | Polyacrylate | |
| Volume | 150 ml | 350 ml | 300 ml | 62.5 ml | 300 ml | 300 ml |
| Priming volume | 1000 ml (2 columns) | 300 ml | 72,5 ml | 290 ml | ||
| Capacity | N/A | 3 l Plasma: 15 nmol anti-ACh-AK (= 10 ng IgG) | 557 mg IgG/Adsorber | 1,2 g IgG/Adsorber | 4 g IgG/Adsorber | 400 mg Immune complexes/ Adsorber |
| Specificity | Anti-ds DNA antibodies, lipids, fibrinogen, immunoglobulins and others | Immunoglobulins, fibrinogen and others | IgG, IgA, IgM | IgG, IgA, IgM | IgG, IgA, IgM | C1q-CIC, C1q-antibodies, anti-phospholipid abs, ibrinogen |
| Preservative | Steam | Steam | 0.1% Thiomersal in buffer pH 7,0 | |||
| Plasma Volume | > 2.5 l | 2 l | 60 - 100 l | > 120 l | 3.5 l | |
| Regeneration | Yes, during one session | No | No | Yes | Yes | No |
| Storage Period | 3 years | 3 years | 18 months | 18 months | ||
| Costs (EUR) | 1,000.00 per adsorber | 650.00 per adsorber | 1,000.00 per adsorber | 10,000.00 per pair | 15,000.00 per pair | 1,900 per adsorber |
Clinical Application of Immunoadsorption
Rapidly Progressive Glomerulonephritis
Plasmapheresis has been shown to be effective in Goodpasture's syndrome [5]. Preliminary results of a controlled trial in Sweden testing immunoadsorption onto protein A versus plasmapheresis in rapidly progressive glomerulonephritis showed no significant difference between both treatments [6]. Usually, renal function cannot be recovered once the patient is dialysis-dependent. However, Schindler et al. reported a 17-year old boy suffering from dialysis-dependent Goodpasture’s syndrome who regained his renal function after immunoadsorption using the Therasorb system [7].Wegeners’ Granulomatosis and Microscopic Polyarteriitis
Two patients with Wegener’s Granulomatosis and 5 patients with microscopic polyarteriitis all with either necrotising glomerulonephritis or glomerular crescents were treated in a case series with a combination of immunoadsorption and conventional cyclophosphamide and prednisolone therapy. One patient with Wegener’s granulomatosis had a stabilisation of the renal function and two patients with microscopic polyarteriitis showed improvement of their renal function while the others either went into end-stage renal failure or died [8]. Segelmark et al. compared plasmapheresis with immunoadsorption onto staphylococcal protein A in patients with ANCA positive vasculitis. In this in vivo study immunoadsorption effectively eliminated ANCAs regardless of the ANCA IgG subclass distribution. Clinically, there was no difference between the plasmapheresis and immunoadsorption group although the immunoadsorption group had higher initial ANCA titres [9].Focal and Segmental Glomerulosclerosis
The lowering of proteinuria and improvement of renal function in recurrent focal segmental glomerulosclerosis using immunoadsorption onto protein A along with the isolation of a proteinuric factor from these patients gave hope for an effective treatment in this condition [10;11]. However, only a subgroup of patients with FSGS demonstrates the proteinuric factor and immunoadsorption does not generally result in long-term remission [12;13].Other Glomerular Diseases
Immunoadsorption was applied in membranous glomerulonephritis [14] and Schönlein-Henoch purpura [15] without convincing effects.Anti-HLA Antibodies in Transplant Recipients and Pre-Transplant Patients
In patients with acute vascular rejection after renal transplantation immunoadsorption can be used to remove anti-HLA antibodies in combination with conventional anti-rejection therapy. Twenty-three patients with biopsy confirmed acute humoral rejection after kidney transplantation were treated with immunoadsorption onto protein A. In 22 patients a negative crossmatch was achieved by this method. However, in six patients the clinical course was complicated by cytomegalovirus antigenaemia [16]. These results were confirmed by another group [17] and in general, it seems feasible to apply immunoadsorption instead of plasmapheresis for acute, vascular rejection although a controlled trial should demonstrate whether one or the other is more effective and associated with less adverse effects.Immunoadsorption could also be successfully
used for the reduction of anti-HLA antibody titre before transplantation
to obtain a negative cross match in highly sensitised patients [18].
These patients would otherwise hardly receive an organ.
Thrombocytopenic Purpura and Haemolytic Uraemic Syndrome
Approximately 20 % of patients with autoimmune thrombocytopenic purpura do not respond to corticosteroids and/or spleenectomy. Good results can be obtained in these patients using immunoadsorption [19]. Gutensohn [20] compared the efficiency of immunoadsorption in patients suffering either from idiopathic thrombocytopenic purpura or from thrombocytopenia refractory to platelet transfusions following bone marrow transplantation. In contrast to Snyder who processed only up to 2 l of plasma, intensive high-volume immunoadsorption seemed to be mandatory to achieve good clinical response in the latter condition. An increase in platelet counts, decrease in haemolysis and stabilisation of renal function could be achieved by immunoadsorption in patients suffering from cancer chemotherapy-associated haemolytic uraemic syndrome [21]. The intermediate results of an ongoing study [22] were encouraging, since haemolysis could be stopped in 14 out of 19 patients.Systemic Lupus Erythematosus
Immunoadsorption was applied to lupus patients for quite a while, but two randomised, controlled trials comparing plasmapheresis as an additive [23]or an induction therapy [24] did not prove to be effective. As a consequence, extracorporeal treatment for systemic lupus erythematosus is not considered as a therapeutic option in most centres. However, conventional treatment with cyclophosphamide and prednisolone does not cure lupus. Patients with prolonged survival bone marrow depression due to cyclophosphamide is more often observed. These patients, patients who must avoid cytotoxic drugs for medical reasons and patients suffering from life-threatening lupus may benefit from alternative extracorporeal treatments. A randomised trial to compare phenylalanine (IM-PH350) adsorption with anti-human Ig (Ig-Therasorb) adsorption in 20 patients showed that SLAM scores in the phenylalanine group decreased from 14.3+/-5.6 to 9.2+/-6.2 after one month and to 9.4+/-3.9 after 6 months while corresponding scores in the Ig-Therasorb group were 18.3+/-5.5 at the beginning, 11.2+/-7.6 after one month, and 9.2+/-2.9 after 6 months [25]. Unfortunately no control group with conventional immunoadsorption was included into the study protocol. Immunoadsorption onto a modified dextran sulphate adsorber (Selesorb) is meanwhile approved as an appropriate treatment in Japan. Selesorb was officially introduced for this indication in the EU this year. Extensive in vitro and in vivo studies regarding the antibody elimination and clinical effects [26-28] are known but no controlled trial has yet been performed. Its effect is mainly restricted to the elimination of anti-ds-DNA antibodies while other immunoglobulins are less likely to be removed. In a single patient with severe skin and small vessel involvement this results were confirmed in our centre. Immunoadsorption onto protein A sepharose in combination with cyclophosphamide and prednisolone was applied to three patients with lupus nephritis. All patients who initially were dialysis-dependent regained their renal function [8;29]. Immunoadsorption onto protein A has a higher affinity to circulating immune complexes and kinetic studies disclose that patients suffering from immune complex mediated lupus vasculitis might show the best benefit [2]. The selective immune complex adsorber Miro [30] aims at the selective removal of pathological immune complexes in active lupus disease. A multi-centre controlled clinical trial is currently being performed by Fresenius, testing the clinical effect of this device.Rheumatoid Arthritis
Rheumatoid arthritis is associated in 75% of the patients with anti-idiotypic IgG or IgM (rheumatoid factors). Circulating immune complexes, antinuclear antibodies and cryoglobulines were also detected in the patients’ sera. Nine out of 11 patients with rheumatoid arthritis undergoing immunoadsorption onto protein A silica showed improvement of their symptoms without change of their anti-inflammatory medication [31]. A subsequent sham apheresis controlled, double-blinded, clinical trail enrolling 99 patients showed a significant benefit for the apheresis group treated with Prosorba. Although only one treatment session per week for 12 weeks was performed, the overall response in the Prosorba group was 29% versus 11% in the sham apheresis group [32]. In analysing only those patients who completed the course of 12 treatments, 41.7% of patients treated with the Prosorba column responded as compared to 15.6% in the sham apheresis group. Thus, immunoadsorption onto protein A should be considered in either severe or treatment-resistant rheumatoid arthritis.Future Developments
The role of immunoadsorption in the near future will be characterised by the development of more specific adsorbers, i.e. adsorbers for immune complexes, specific autoantibodies or antibodies against xenografts. It is imaginable that immunoadsorption will be integrated into a concept of immunomodulatory treatment for autoimmune disease side by side with immunosuppression, autologous stem cell or T cell transplantation and selective immune deviation.One major drawback in the field of extracorporeal immunoadsorption is
the lack of controlled clinical trials. At present, clear indications for
its application can only be drawn from uncontrolled case series and previous
studies using plasma exchange. However, both treatments are different with
respect to efficiency, selectivity and adverse effects. If no controlled
data will be available soon, immunoadsorption might be subject to an exotic
outsider method and treatment will not be re-financed.
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