The Role of Immunoadsorption in Clinical Nephrology
Norbert Braun and Teut Risler
Sektion Nieren- und Hochdruckkrankheiten of the Universitätsklinikum
Corresponding Author's Address
Dr. Norbert Braun, MD
Sektion Nieren- und Hochdruckkrankheiten
Leiter: Prof. Dr. T. Risler, MD
Tel.: ++49 7071 2983172
Fax: ++49 7071 293174
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% . 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 . 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 . 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 . 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,
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
|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|
|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 (=2.2 g 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|
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 .
These patients would otherwise hardly receive an organ.
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.
6 Stegmayr BG, Almroth G, Berlin G, Fehrman I, Kurkus J, Norda R, Olander R, Sterner G, Thysell H, Wikstrom B, Wiren JE: Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis - A Swedish multi-center study. Int.J Artif.Organs 1999;22:81-87.
8 Palmer A, Cairns T, Dische F, Gluck G, Gjorstrup P, Parsons V, Welsh K, Taube D: Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption, prednisolone and cyclophosphamide. Nephrol Dial.Transplant 1991;6:536-542.
9 Kjellberg BM, Segelmark M, Freiburghaus C: A comparative study between plasma exchange and immunoadsorption on the removal of ANCA. 2nd International Congress of the International Society for Apheresis 1999;104-104.(Abstract)
10 Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, de Ligny BH, Niaudet P, Charpentier B, Soulillou JP: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl.J Med 1994;330:7-14.
11 Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl.J Med 1996;334:878-883.
12 Rosenfeld, S., Braun, N., DiNicuolo, A., Guagnin,
M., and Risler, T. Kinetics of immunological and biochemical parameters
during protein-A immunoadsorption in patients with recurrent focal and
segmental glomerulosclerosis. Murase, S., Taniguchi, Y., Mukai, J., Ishikawa,
H., Tsudal, M., Yamamura, M., and Takada, T. Proceedings of the 2nd Internet
Congress on Biomedical Science (CD-ROM publication) . 1996. Tokio, Japan,
Ref Type: Electronic Citation
13 Haas M, Oberbauer R, Borchhardt K, Druml W, Mayer G: Variable effects of plasma protein adsorption on glomerular permselectivity in primary focal and segmental glomerulosclerosis. J Am Soc.Nephrol 1995;6:1014-1014.(Abstract)
15 Schmaldienst S, Winkler S, Breiteneder S, Hörl WH: Severe nephrotic syndrome in a patient with Schönlein-Henoch purpura: complete remission after cyclosporin A. Nephrol Dial.Transplant 1997;12:790-792.
16 Pretagostini R, Berloco P, Poli L, Cinti P, Di-Nicuolo A, De-Simone P, Colonnello M, Salerno A, Alfani D, Cortesini R: Immunoadsorption with protein A in humoral rejection of kidney transplants. ASAIO J 1996;42:M645-M648
17 Hickstein H, Korten G, Bast R, Barz D, Templin R, Schneidewind JM, Kittner CH, Nizze H, Schmidt R: Protein A immunoadsorption (IA) in renal transplantation patients with vascular rejection. Transfus.Sci. 1998;19 Suppl. S:53
18 Higgins RM, Bevan DJ, Carey BS, Lea CK, Fallon M, Bühler R, Vaughan RW, OÇDonnell PJ, Snowden SA, Bewick M, Hendry BM: Prevention of hyperacute rejection by removal of antibodies to HLA immediate before renal transplantation. Lancet 1996;348:1208-1211.
19 Snyder HW, Jr., Cochran SK, Balint JP, Jr., Bertram JH, Mittelman A, Guthrie TH, Jr., Jones FR: Experience with protein A-immunoadsorption in treatment- resistant adult immune thrombocytopenic purpura. Blood 1992;79:2237-2245.
20 Gutensohn K, Zander AR, Rowley SD, Hester J, Kuehnl P: Protein A immunoadsorption in alloimmunized patients refractory to platelet transfusions and in patients with treatment-resistant immune thrombocytopoenic purpura. Transfus.Sci. 1998;19 Suppl. S:47-52.
21 Snyder HW, Jr., Mittelman A, Oral A, Messerschmidt GL, Henry DH, Korec S, Bertram JH, Guthrie TH, Jr., Ciavarella D, Wuest D, et al.: Treatment of cancer chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma. Cancer 1993;71:1882-1892.
23 Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM: A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group [see comments]. N Engl.J Med 1992;326:1373-1379.
24 Wallace DJ, Goldfinger D, Pepkowitz SH, Fichman M, Metzger AL, Schroeder JO, Euler HH: Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis. J Clin Apheresis 1998;13:163-166.
25 Gaubitz M, Seidel M, Kummer S, Schotte H, Perniok A, Domschke W, Schneider M: Prospective randomized trial of two different immunoadsorbers in severe systemic lupus erythematosus. J Autoimmun. 1998;11:495-501.
26 Matsuki Y, Suzuki K, Kawakami M, Ishizuka T, Kawaguchi Y, Hidaka T, Nakamura H: High-avidity anti-DNA antibody removal from the serum of systemic lupus erythematosus patients by adsorption using dextran sulfate cellulose columns. J Clin.Apheresis. 1996;1996;@11:30-35.
27 Suzuki K, Taman J, Matsuki Y, Hidaka T, Ishizuka T, Kawakami M, Yabuki T, Kutsuki H, Nakamura H: Anti-dsDNA antibody kinetics during in vivo apheresis in systemic lupus erythematosus patients and in an in vitro apheresis model. J Clin Apheresis 1996;11:211-216.
28 Suzuki K, Matsuki Y, Hidaka T, Ishizuka T, Kawakami M, Takata S, Kutsuki H, Nakamura H: Anti-DNA antibody kinetics following selective removal by adsorption using dextran sulphate cellulose columns in patients with systemic lupus erythematosus. J Clin.Apheresis. 1996;11:16-22.
31 Wiesenhutter CW, Irish Bl, Bertram JH: Treatment of patients with refractory rheumatoid arthritis with extracorporeal protein A immunoadsorption columns: a pilot trial. J.Rheumatol. 1994;21:804-812.
32 Felson DT, La Valley MP, Baldassare AR, Block JA, Caldwell JR, Cannon GW, Deal C, Evans S, Fleischmann R, Gendreau M, Harris ER, Matteson EL, Roth SH, Schumacher HR, Weisman MH, Furst DE: The Prosorba column for treatment of refractory rheumatoid arthritis. Arthritis Rheum. 1999;42:2153-2159.