World apheresis registry.
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Biomedical subjects
Publications and source records attributed to W Ramlow.
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In 2002 WAA decided to start a world-wide apheresis registry to gain insight into the extent of treatment, adverse events, and to facilitate contacts among centers when treatment indications are rare and experience limited. Stem cell and other blood products collections intended for therapeutic application can also be entered. The WAA planned to use the French Registry. Its translation into English has not been accomplished and the fiscal obligations for that registry has not, as yet, been determined or considered and approved by the WAA Board. From Dec 2002 the proposed registry (a merged version of the French, Canadian and Swedish registries) can be immediately implemented. We now cordially invite all centers to join that registry. Please, also inform colleagues at other centers in your country to join. E-mail and address lists of colleagues in your country who have not registered will be welcomed. The site is at: Go to World Apheresis Registry; Login code to test the Registry is: al61tms. Then apply for a specific login code for your center. We welcome you to this registry for your input of data. You will not be charged any registration fee. The registry includes a randomization system that can be used for local or multi center studies (randomization by in-center basis allows you to make your own studies). It includes a formula that increases the chance to get a more even distribution between groups also for smaller sample sizes.
Eight years ago four patients suffering from myasthenia gravis (MG) type C and E according to Compston with failed drug therapy were treated three times (one patient 11 times) by protein A immunoabsorption (Immunosorba, Excorim, Fresenius Hemocare GmbH, StWendel, Germany). No further immunoabsorption treatments have been carried out. In addition, three patients were given a thymectomy. The present status of the patients was checked six and eight years thereafter. We could see a beneficial effect in all MG patients. The patients are fit for work; all have an improved Besinger index. The patients were used as their own controls. A higher anti-AChR-ab level six years after protein A immunoabsorption than at the beginning was seen in all patients combined with a less serious MG. In addition, their immunomodulation could be induced as seen in lymphocyte and inflammatory protein changes during the first 36 days after beginning immunoabsorption treatment. A larger population has to be investigated to verify these results.
Particle contamination of blood always takes place in extracorporeal systems and few studies have been conducted to evaluate potential risks. Particle concentration was measured in the efferent blood line on original equipment for two established LDL elimination procedures (DALI) (Fresenius) and Liposorber (Kaneka). Acquired data were compared with standards for infusion solutions from European (EP) and American (USP) Pharmacopoeia. All values were well below the given limits. Even in extreme situations (>20 pump stops) particle concentration did not exceed the standards. Considering an average treated blood volume of 7.31 for the DALI-System and 17.01 for Liposorber (long term clinical studies) the absolute amount of particles infused per treatment was 167,000 (DALI) and 465,000 (Liposorber) particles > or = 2 microm.
Protein A (SPA), a major cell wall component of Staphylococcus aureus, has occupied numerous investigators from its discovery in the late fifties. Its availability and avid binding to human immunoglobulins have led to extensive usage for diagnostic and research purposes. Today, SPA-based extracorporeal immunoadsorption relies on two rather different systems, namely, SPA-silica (Prosorba), and SPA-Sepharose (Immunosorba). Both systems are approved by the Food and Drug Administration for the core indications of rheumatoid arthritis and idiopathic thrombocytopenic purpura (SPA-silica) or hemophilia with inhibitors (SPA-Sepharose). Off label indications include immune disorders with a conceivable connection between autoantibody titers and disease activity, like forms of glomerulonephritis, systemic lupus erythematodes, myasthenia, and the Guillain-Barré syndrome as well as alloantibody formation in the context of e.g., transplantation. This review summarizes historical developments and important properties of SPA. Indications for extracorporeal therapy are discussed on the basis of available information and personal experience.
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 micromol/L to 100 micromol/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.
Endocrine ophthalmopathy (EO) is a severe disease entity that is characterized by retrobulbar swelling due to accumulation of glycosaminoglycans on an autoimmune basis. This disorder can lead to the loss of vision and often is resistant to conventional therapy. There is a relation to Graves' hyperthyroidism, but probably no close association. Two patients with severe EO that was resistant to usual therapeutic approaches including steroids and radiological and surgical measures underwent a 20 session course of intensive immunoadsorption therapy (Plasmaselect/Therasorb Anti-IgG) with a mean 2- to 3-fold plasma volume treated. After the first sessions, both patients voiced an impressive relief of their major symptoms, which was confirmed by ophthalmological investigation. Throughout the time of therapy until present, these patients have remained at their respective levels of improvement. We consider immunoadsorption an effective therapeutic opportunity in severe EO resistant to conventional treatment.
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Elimination of IgG can be achieved by extracorporeal immunoadsorption (IA) based on specific binding to either staphylococcal protein A (Excorim) or sheep polyclonal antibodies directed against human IgG (Therasorb). In 602 analyzed sessions of IA, elimination of IgG was 60% through 80% depending on the treated plasma volume, with no significant difference between the mentioned systems. However, the decrease of IgM and IgA was approximately 50% in the anti-IgG compared to 20-40% in the protein A system. Plasma albumin concentration decreased by 20% in the anti-IgG system compared to 15% in the protein A system, and hemoglobin values increased by 2% in the anti-IgG system and decreased by 6% in the protein A system. In conclusion, a clinical relevance for these findings cannot be ruled out, and the individual choice might depend on the clinical situation and laboratory findings.
Release of microparticles into the blood during extracorporeal circulation must be kept low because of possibly serious acute and chronic adverse effects. Concentration and size distribution of microparticles were measured during simulated treatments (n = 7) on original equipment for 2 standard low-density lipoprotein (LDL) elimination procedures (DALI 750, Fresenius AG, St. Wendel, Germany and Liposorber, Kaneka Corporation, Osaka, Japan) and compared to hemofiltration solutions. For both systems as well as in hemofiltration solutions, the mean particle concentrations in 500 ml portions gathered from the efferent blood line stayed below 10% of pharmacopoeia standards for infusion solutions (United States Pharmacopoeia, European Pharmacopoeia) in all measured size classes. Although particle concentrations were comparable in all systems, the mean total number of particles > or =2 microm released per session was lowest in the DALI (167,000) compared to the Liposorber (465,000) and hemofiltration solutions (2,240,000). This was mainly due to different total processed blood volumes necessary to achieve the required LDL reduction.
Intracellular cytokine staining and flow cytometry were used to investigate whether immunoadsorption (IA) of immunoglobulins alters intracytoplasmic cytokine production in CD4+ and CD8+ T cells from the blood of patients with refractory rheumatoid arthritis (n = 7), membrane proliferative glomerulonephritis (n = 1), and Goodpasture's syndrome (n = 1). Four patients (Group 1) showed severely depressed production of TNF-alpha, IL-2, IFN-gamma, and IL-4 by CD4+ and CD8+ T cells and responded to 3 IA sessions with significant increases in CD4+TNF-alpha+, CD4+IL-2+, and CD8+IL-2+ T cells. Also, a tendency toward increased percentage levels of CD4+ T cells producing IFN-gamma or IL-4 and of CD8+ T cells producing either TNF-alpha or IFN-gamma was seen, but due to the small number of patients investigated, these differences did not attain statistic significance. Group 2 (n = 5) showed unimpaired intracellular cytokine levels and responded to IA with a heterogeneous pattern of changes in TNF-alpha, IL-2, IFN-gamma, and IL-4 production, but these alterations were smaller than those in Group 1. The present findings indicate that the extracorporeal removal of immunoglobulins by anti-IgG or protein A adsorber columns has an impact on T cell immunity and suggest that modulating effects on cellular immune system function are involved in the mode of action of IA.
The classical immune complex-mediated disease, termed serum sickness, developed a short time after the injection of horse anti-tetanus toxin. Antibodies against circulating horse plasma proteins lead to the formation of immune complexes within the blood circulation (CIC). The inflammatory response, including systemic complement activation and vasculitis, seriously affected the function of all organs, including the most susceptible kidney. Meanwhile CIC have been detected in almost every systemic disease, including autoimmune disorders and also cancer and infections. This brief review will focus on the rationale and the equipment for extracorporeal elimination of CIC.
Six years ago 4 patients suffering from myasthenia gravis (MG) types C and E according to Compston with failed drug therapy were initially treated 3 times (1 patient, a total of 11 times) by protein A immunoadsorption (Immunosorba, Excorim AB, Lund, Sweden). No further immunoadsorption treatments have been carried out. In addition, 3 patients were given a thymectomy. The present status of the patients was checked. We could see a beneficial effect in all MG patients. The patients are fit for work; each has an improved Besinger index. The patients were used as their own controls. A higher anti-AChRAb level 6 years after protein A immunoadsorption than at the beginning was seen in all patients, combined with less serious MG. In addition, their immunomodulation could be induced as seen in lymphocyte and inflammatory protein changes during the first 36 days after beginning immunoadsorption treatment. A larger population has to be investigated to verify these results.
A 46 year old woman suffers from chronic progressive multiple sclerosis. She was diagnosed in 1993. Because of many complications seen in conservative treatment, plasma exchange was started. The expanded disability status scale by Kurtzke could be improved but the interval between the treatments became shorter and shorter. It was therefore decided to commence protein A immunoadsorption treatment. With this treatment the patient shows good and stable improvement in neurological and functional status with an acceptable treatment frequency of once every 3 weeks.
With on-line formation of the substitution fluid, high substitution rates in predilution (PRD) and postdilution (POD) can be obtained (Fresenius 4008 On-Line HDF; Gambro AK 100 Ultra). The substitution fluid is branched off from the dialysate produced by the dialysate delivery system of the HDF machine. Under these conditions it is desirable to consider the effect of the different treatment modes on the acid-base status. Using Fresenius 4008 On-Line HDF machines, ESRD-patients were treated alternately with high-flux hemodialysis (HD), postdilution HDF (POD-HDF) and predilution HDF (PRD-HDF), while all other treatment parameters were kept constant, in particular the bicarbonate dialysate concentration. Plasma-HCO3, -pH and -pCO2 were measured and compared with the results of a multicompartment bicarbonate model developed by Thews. Also plasma-pO2 and K+ were measured. The results showed no significant differences between HD, POD- and PRD-HDF. Acidosis was corrected effectively and no excessive compensation of the acid-base disturbance was observed.
Since the introduction of on-line substituate preparation, high substituate rates (Qs) in pre- and postdilution for hemodiafiltration (HDF) procedures can be realized. During postdilution HDF (POD-HDF) and additional convective removal is possible, but in vivo Qs is limited to approx. 1/3Qb (bloodflow). With predilution HDF (PRD-HDF) higher Qs and therefore high convective transport rates by ultrafiltration can be reached. On the other hand the blood concentration is diminished by predilution. Further decrease of the diffusive transport is caused by reduced dialysate flow Qd due to separation of the substituate from the dialysate (Fresenius 4008 On-Line HDF, Gambro AK100 Ultra). The theoretical description of the combined diffusive-convective transport is limited to 1-dimensional models and small UF-rates. Therefore for practical and theoretical purposes the assessment of the efficacy of on-line PRD-HDF and POD-HDF in different molecular weight ranges is desirable. By means of in vitro experiments the effective clearances Keff of hemodialysis (HD, dialyzer: Fresenius F60) for urea, creatinine, vitamin B12 and inulin were compared with measured and theoretical Keff of POD- and PRD-HDF. The theoretical expectation is confirmed that Keff for small molecular weight substances decreases slightly with PRD-HDF and increases for larger molecules. In the case of POD-HDF Keff for small molecular weight substances increases slightly and strongly for larger molecules. In vivo experiments were performed to measure the real substance removal from patient's blood and to figure out the impact of dialysate flow (collection of the used dialysate during the 1. treatment hour and concentration measurements for urea, creatinine, phosphate, beta 2-MG). The results show that the subtraction of Qs from Qd reduces Keff for urea, creatinine and phosphate but not for beta 2-MG. PRD-HDF with Qd = 500 ml/min is significantly less effective for small molecules than HD. There is no significant difference of Keff for urea, creatinine, phosphate during HD and PRD-HDF with Qd = 800 ml/min, but a significant increase of 10-15% for POD-HDF. Keff for beta 2-MG increases by 75% for PRD-HDF and 95% for POD-HDF compared with HD (Qd = 500 ml/min).
The protein A immunoadsorption allows to remove antibodies of the classes IgG, IgM and IgA in special quantities from the plasma. IgG subclasses 1, 2 and 4 will be removed for 100% and IgG of class 3 for nearly 80%. For this reason immunoadsorptions are a useful therapeutic method especially for immunological diseases with antibodies of IgG type. The successful use of immunoadsorption in the removal of HLA antibodies in patients with acute myeloic leukemia and patients after kidney allograft is reported.
The removal of protein-bound substances of pathogenetic relevance from blood is of therapeutic interest for drug intoxications, renal and liver failure, and metabolic disorders. Current methods using adsorbents are effective but often not specific enough. This work presents an alternative method that enables the dialyzability of albumin-bound toxins from plasma by the use of a high-flux dialyzer (F 60 Fresenius) and an albumin solution circulating on the dialysate side to increase selectively the affinity for albumin-bound toxins. This method resulted in effective removal of unconjugated bilirubin, drugs with a high protein-binding ratio (sulfobromophthalein, theophylline), and a protein-bound toxin (phenol). The additional removal of PBS could extend the applicability of dialysis, for example, to drug intoxications and liver failure or could improve the elimination of protein-bound uremic toxins in chronic renal failure.