Membranes for therapeutic apheresis.

Kuraray has developed many kinds of apheresis devices, such as plasma separators, plasma fractionators, and apheresis monitors. In this article, apheresis membranes, especially double filtration plasmapheresis (DFPP) and plasma fractionators used in DFPP are introduced. DFPP is both clinically and cost effective apheresis therapy, and it has been used widely for the treatment of many kinds of diseases. Several types of plasma separators with various pore sizes are available. It is important to select the proper plasma separator with suitable pore size, determined by the size of the pathogenic substances to be removed. The Evaflux 5A ethylene-vinyl alcohol copolymer plasma fractionator efficiently separates low-density lipoprotein from high-density lipoprotein. DFPP with the Evaflux 5A is effective for the treatment of familiar hyperlipidemia.     

Double filtration plasmapheresis for the treatment of bullous pemphigoid: a three case report.

Bullous pemphigoid (BP) is an autoimmune disease caused by an antidermal basal lamina antibody. In recent years double filtration plasmapheresis (DFPP) has been reported to be an effective therapy for BP. We experienced 3 cases of BP treated by DFPP. DFPP resulted in an improvement in clinical symptoms and remission allowing a decrease in the required dose of corticosteroid. DFPP was found to be an effective treatment for all 3 patients without noticeable adverse events resulting from DFPP. From these results it is concluded that DFPP is worth considering as an option as treatment for BP patients who were unresponsive to conventional steroid therapy, those in whom corticosteroids should be reduced or discontinued because of complications such as diabetes mellitus and/or osteoporosis.     

Therapeutic apheresis in multiple sclerosis

Therapeutic apheresis is divided in cytapheresis and plasmapheresis. And plasmapheresis(PP) is divided into three treatments, plasma exchange(PE), double filtration plasmapheresis(DFPP) and immunoadsorption plasmapheresis(IAPP). PE has been applied in the neuroimmunological disorders and the effectiveness of PP has been well established in some neuroimmunological disorders. In this article, PP treatment of multiple sclerosis(MS) was reviewed. PP is an effective means of removing the pathogenic immune-mediated factors, such as inflammatory cytokines, autoantibodies, immune complexes, and complements. PP may affect not only humoral immune responses but also cellular immune responses. Previous clinical reports suggested that PE might be effective in treating acute attacks of MS, but be no effective in patients with chronic progressive MS. IAPP may be superior to PE in the treatment of MS.     

The efficacy of plasmapheresis or leukocytapheresis for articular and extraarticular manifestations of rheumatoid arthritis.

The authors investigated the clinical effectiveness of plasmapheresis (PP) or leukocytapheresis (LP) in 21 patients with articular or extraarticular manifestations of rheumatoid arthritis (RA). Salt-amino acid coprecipitation (SAC) or double membrane filtration plasmapheresis (DFPP) were used as PP regimens, and a centrifugation method (CS-3000) and leukocyte removal filter (Cellsorba) were used as LP regimens. The results were as follows. The removal rate of plasma globulin was higher with SAC than with DFPP, and the removal rate of leukocyte was higher with Cellsorba than with CS-3000. Based on a comparison of the present apheresis methods for short-term therapy, the leukocyte removal regimen proved more effective than the PP regimen by DFPP. In patients with extraarticular manifestations of malignant rheumatoid arthritis (MRA), there were rapid and dramatic intractable skin ulcers, rheumatoid nodules, low serum levels of complements, and high levels of immune complex. Cellsorba was the more useful regimen in short-term apheresis therapy as compared with DFPP. In RA or MRA patients receiving the long-term PP or LP regimen obvious improvements in grasping power and C reactive protein (CRP) levels were observed. The PP or LP regimen continuation rate was 88, 79, and 54% at 3, 12, and 20 months, respectively.     

Experience of double filtration plasmapheresis in the treatment of Guillain-Barré syndrome

Therapeutic plasma exchange (TPE) is a standard treatment in Guillain-Barré syndrome. TPE may require exogenous fluid for replacement of plasma and, depending on the equipment used, varying extracorporeal volumes. Potential adverse effects include allergic reaction, infection, and hypotension. From September 1993 to December 1997, we treated 16 patients with Guillain-Barré syndrome by a newly developed method of automated double filtration plasmapheresis (DFPP). Patients (ten males and six females, age ranged from 16 to 73) suffering from acute ascending motor weakness and fulfilling the diagnostic criteria for GBS were chosen for DFPP. Each patient received at least five sessions of apheresis in 7 to 10 days and approximately 2.5 to 3.0 L of plasma was treated in each session. Patients were evaluated by disability grade according to a Hughes scale. The mean grade of disability was 3.62 at treatment and improved to 2.37 four weeks after the start of DFPP. The median time to grade 2 (walk without support) was 19 days. There were five patients (41.6%) in need of respirator support. The median time to weaning off the respirator was 9 days. Only two patients (12.5%) could not reach grade 2 at the end of 6 months. Our results were comparable to previously published results of TPE. We conclude that DFPP may be as effective as TPE in the treatment of GBS. J. Clin. Apheresis 14:126–129, 1999. © 1999 Wiley-Liss, Inc.     

Double filtration plasmapheresis – 10-year pediatric experience as an alternative to plasma exchange

BackgroundDouble filtration plasmapheresis (DFPP) is more selective at removing antibodies compared to plasma exchange (PE), thus reducing the need for replacement blood products.MethodsWe retrospectively analyzed the records of all pediatric patients whom DFPP had been performed.ResultsIn total, 30 patients were treated with DFPP. Data were available for 436 sessions in 23 patients. Patients had a median of 6 (1–161) sessions. Age at start of treatment was 13.9 years (2.2–19.2) and weight 46 kg (13.4–82.8).Six patients were treated for antibody mediated rejection; 1 had full recovery, 1 CKD stage 4 and 4 required dialysis. Two patients were treated for recurrence of focal segmental glomerulosclerosis (FSGS) with good response. One successfully had an ABO-incompatible kidney transplantation. Five had anti-glomerular basement membrane disease; 3 had complete recovery, 1 CKD and 1 required transplantation. Three had granulomatosis with polyangiitis; 1 with full recovery, 1 had CKD and 1 required dialysis. Two had Type-2 Membrano-proliferative glomerulonephritis, 1 successfully treated, the other needing dialysis. One treated for rapidly progressive MPO-glomerulonephritis required dialysis. Other indications were Myasthenia Gravis, Guillain-Barré disease and autoimmune limbic encephalitis.Excluding FSGS patients (with >100 sessions), one patient had cryoprecipitate, 2 had blood transfusions, no other blood products were required. Minor complications were seen in 13 sessions (8.4%). No major complications were seen.ConclusionDFPP is a safe, well tolerated form of apheresis that appears to have comparable outcomes to that of PE, without the routine need of replacement blood products.     

Double filtration plasmapheresis in critical care.

Many kinds of technologies have been introduced and successfully developed for therapeutic apheresis. Furthermore, several kinds of these technologies have also been applied in critical care. Double filtration plasmapheresis (DFPP), however, is rarely applied in this field in comparison with other treatments such as continuous hemofiltration, continuous hemodiafiltration, single filtration plasmapheresis, and plasma adsorption therapies. In this paper, the characteristics of the DFPP treatments for critical care are summarized. During the DFPP treatments, the patient's blood volume (BV) often decreases with time due to albumin loss induced by inadequate albumin infusion in a supplementation fluid. We examined the change of BV by a continuous hematocrit monitor, Crit-Line, during an in vivo study for 9 patients. As a result, albumin loss fairly occurred in DFPP treatments. The decrease of patient BV was induced by an oncotic pressure drop due to albumin loss and often resulted in a blood pressure drop. This is a serious problem for DFPP in critical care. We should avoid inadequate albumin infusion if the patient is suffering from these adverse effects. In order to determine the optimal concentration C(S) and volume V(S) values of a supplemented albumin solution, we introduced a variable blood volume model for albumin transport in DFPP.     

Resistant oral mucosal lesions in pemphigus vulgaris responsive to double filtration plasmapheresis: First case report from Turkey

BackgroundAdjuvant therapeutic methods are employed when pemphigus vulgaris (PV) fails to be controlled by conventional corticosteroid treatment. Objective: The efficacy of double filtration plasmapheresis (DFPP) was investigated in a PV patient with severe, refractory mucosal disease.MethodsA total of 3 DFPP cycles, each cycle consisting of 5 double filtration sessions conducted on alternate days was completed.ResultsDFPP provided immediate clinical relief of symptoms as well as a significant decrease in anti-desmoglein antibody levels and allowed for a much lower corticosteroid dose.ConclusionDFPP was an effective and safe adjuvant therapy in our patient with PV and it offers a valid treatment option in PV patients with recalcitrant disease.     

Plasma adsorption in critical care.

Plasmapheresis therapies such as plasma exchange (PE), double filtration plasmapheresis (DFPP), or immunoadsorption plasmapheresis (IAPP) have become therapeutic tools in critical care. PE or DFPP are limited by their non- or semiselective removal of all plasma components. Replacement fluids such as fresh frozen plasma and albumin are necessary during PE or DFPP. There is the risk of infection and allergic reactions whenever such fluids are used. On the other hand, IAPP is superior to PE and DFPP because it does not require any replacement fluid. There has been development of many adsorbent columns used for removing specific pathogenic substances, and patients with various kinds of critical illness have been treated with IAPP. However, IAPP can be applied only for certain diseases because of the limitations of the commercially available columns. It is concluded that the development of new adsorption therapy may improve the high mortality and morbidity rate in critically ill patients.     

The use of emergency apheresis in the management of plasma cell disorders

Hyperviscosity syndrome (HVS) develops most commonly in Waldenström's macroglobulinemia (WM) and multiple myeloma (MM). Plasmapheresis is the immediate therapy and very effective at relieving symptoms by removing paraprotein. The most commonly used replacement fluid is 4%–5% human albumin in physiologic saline. FFP may be used in patients with coagulation abnormalities. Plasmapheresis should be continued until acute symptoms abate. Hyperviscosity impairs the circulation in the retina and causes hemorrhages around the small retinal vessels. Early diagnosis and urgent plasmapheresis may reduce blindness caused by retinal hemorrhages and/or retinal detachment. In HCV related mixed cryoglobulinemias, plasmapheresis is indicated if rapidly evolving life-threatening disease with immunosuppressive agent exists. In non-infectious mixed cryoglobulinemia plasmapheresis is indicated when the disease manifestations are severe, as a second line option. In WM patients with hyperviscosity symptoms and IgM?>?4?g/dL, preemptive plasmapheresis is recommended to prevent an IgM flare with rituximab. Certain IgG/A MGUS-associated neuropathy patients may benefit from plasmapheresis. For cast nephropathy (suspected or biopsy proven), plasmapheresis is recommended when the sFLC?≥?500?mg/l and as early as possible (<1 month with kidney injury). Theoretically, extracorporeal removal alone, without efficient tumor killing, could not reduce sFLC due to high production by the tumor mass and rapid rebound between compartments.     

Comparative study of clinical effects between plasma adsorption and double filtration plasmapheresis in patients with myasthenia gravis.

Plasma exchange (PE) has been one of the most powerful treatments for patients with myasthenia gravis (MG) since Pinching et al. reported its clinical usefulness in 1976, despite the need for supplemental human plasma. However, new apheresis techniques, e.g., plasma adsorption (PA) and double filtration plasmapheresis (DFPP), which do not need human plasma, were developed and have been introduced for clinical use in MG. We compared the effects of these plasma purification therapies in patients with MG and found that DFPP improved such subjective symptoms as chest compression and general fatigue better than PA while both of them could decrease the serum level of acetylcholine receptor (AChR) antibodies and relieve objective muscle weakness to a similar degree. It may be that DFPP can remove some circulating pathogenic factors other than AChR antibodies more efficiently than PA.     

Lipidfiltration––safe and effective methodology to perform lipid-apheresis

Familial hypercholesterolemia (FH) not adequately responding to diet and drug therapy represents an indication for extracorporeal lipid-apheresis, which has become an highly effective and approved therapy for those patients in several countries. Based on different methodology, five treatment options of lipid-apheresis exist and are in widespread practical use covered by regular reimbursement in Germany. All methods are safe and demonstrate equivalent efficacy of reducing LDL cholesterol with respect to the single apheresis session as well as during long-term treatment. Therefore German reimbursement guidelines leave the choice of the method to the discretion of the apheresis center. Related to properties of the used technology all methods exhibit characteristic patterns of additional plasma protein elimination, which do not impair, but in part may increase the therapeutic benefit of lipid-apheresis. Fibrinogen reduction has to be mentioned as an example. The Lipidfiltration system is based on plasmafiltration previously referred to as membrane differential filtration (MDF), synonymous with double filtration plasmapheresis (DFPP). The new term Lipidfiltration was the result of technological progress in the manufacturing process of the plasmafilter resulting in enhanced sieving characteristics and capacity. The Lipidfiltration system is completed by a specifically designed therapy machine with optimised performance characteristics.     

The single center registry for therapeutic apheresis in Turkey: 11-year activity

Therapeutic apheresis (TA) is used as primary and adjunctive therapy in the treatment of several diseases and syndromes. We retrospectively evaluated the results of therapeutic apheresis (TA) including therapeutic plasma-exchange (TPE), double filtration plasmapheresis (DFPP), therapeutic thrombocytapheresis and leukocytapheresis as 11-year activity during 2000-2011. A total of 845 TA procedures were performed in 114 patients (67 male and 47 female, with mean age 51±17 years). Adverse events (AE) were seen in 8.6% of procedures. None of the patients died from any complication. TA is safely carried out in our center in several diseases which are similar to previous reports.     

A study of the efficacy of plasmapheresis for the treatment of drug induced toxic epidermal necrolysis.

The efficacy of plasmapheresis for the treatment of toxic epidermal necrolysis (TEN) in our patient and related reports in the literature were examined. The patient, a 41-year-old female, was diagnosed as having drug (Sedes-G [isopropylantipyrin, arylisopropylacetoureid, and phenacetinum]) induced TEN. Upon admission to our hospital, extensive corticostroid therapy was initiated. After 6 days, because more than 90% of the patient's body surface was affected by TEN, it was concluded that the patient was unresponsive to corticosteroid therapy. Double filtration plasmapheresis (DFPP) was therefore begun. After 2 sessions of DFPP, extensive reepithelialization rapidly occurred, and after 3 sessions of DFPP, the improvement was dramatic. The patient's condition had almost healed during 1 month's hospitalization. It has been reported in the literature that 22 patients with drug induced TEN have been treated with plasmapheresis. The mortality rate of 23 patients, including our patient, was 17.4%. The rate of effectiveness of plasmapheresis on drug induced TEN is 82.6%. It appears that some kind of necrolytic factors were removed by the plasmapheresis. This suggests that plasmapheresis may be an effective treatment for drug induced TEN.     

Plasmapheresis for the treatment of pemphigus vulgaris and bullous pemphigoid.

Forty-two cases of pemphigus vulgaris (PV) and bullous pemphigoid (BP) were treated with plasmapheresis by one of 3 techniques: centrifugation, double filtration plasmapheresis (DFPP), or a combination of the two. Each plasmapheresis resulted in a rapid reduction in the autoantibody titer and an improvement in clinical symptoms, thereby allowing a lower dose of corticosteroid to be administered and remission to be achieved. These findings suggest that plasmapheresis is an effective treatment for PV and BP patients who have been unresponsive to conventional therapy, for those for whom conventional drugs are contraindicated due to complications, and for those who show severe clinical manifestations.     

Selective plasma exchange can reduce auto‐antibodies in patients with bullous pemphigoid without affecting factor XIII and fibrinogen

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder characterized by circulating serum IgG antibodies against two hemidesmosomal proteins: BP180 and BP230. Fundamentally, immunosuppressive therapies are administered to treat this disease, but plasmapheresis can be added for refractory patients. We experienced the case of a 63‐year‐old patient with refractory BP for which we administered double filtration plasmapheresis (DFPP). His skin lesions improved along with decreased IgG BP180 antibodies, but factor XIII (FXIII) and fibrinogen were also reduced by DFPP repetition. Reportedly, deficiency of those factors can cause lethal bleeding. Especially, decreased FXIII cannot be detected by prolongation of bleeding or coagulation time. To prevent further reduction of those factors and bleeding complications, DFPP was switched to selective plasma exchange (SePE), a new modality of plasmapheresis that uses a membrane plasma separator with smaller than ordinary pores. SePE further reduced pathogenic IgG BP180 antibodies, but FXIII and fibrinogen recovered. For this case, we measured the mean of reduction ratios in serum IgG and FXIII both before and after plasmapheresis sessions and detected the decreased levels of FXIII and fibrinogen during DFPP. We were able to switch to SePE from DFPP appropriately before any bleeding event occurred. The utility of SePE was demonstrated, especially for the reduction of pathogenic antibodies with retention of FXIII and fibrinogen, which have the longest half‐lives among coagulation factors and which take a long time to recover.     

Therapeutic apheresis application using membrane plasma fractionation technology: present scope and limitations.

Membrane technologies have been applied for therapeutic apheresis, such as plasma separation and plasma fractionation. Membrane used for plasma fractionation has a microporous structure with pore sizes in the range of 0.01-0.04 microm. A membrane plasma fractionator is utilized for the second filter in the double filtration plasmapheresis (DFPP) system and is applied for treatment of various diseases.This article summarizes the present scope and limitation of membrane plasma fractionation.     

Plasmapheresis for collagen diseases

Recently plasmapheresis has been performed for connective tissue disease. Double-filtration plasmapheresis (DFPP) has mainly been performed for rheumatoid arthritis (RA) and systemic lupus erythematosus (SEL) since 1980. In DFPP, autoantibodies and immune complex are removed by the second filter. The adaptation of plasmapheresis is commonly for cases (1) which are resistant to some medications, (2) which have a high titer of antibodies or immune complex, (3) in which the medication must be decreased or stopped because of side effects and complications, or (4) which are in the acute active phase. We suggest DFPP to be useful as a treatment for connective tissue disease.     

Ability to remove immunoglobulins and antiganglioside antibodies by double filtration plasmapheresis in Guillain-Barré syndrome: is it equivalent to plasma exchange?

The value of plasma exchange (PE) in Guillain-Barré syndrome (GBS) is well established. In Japan, patients with GBS and related diseases often receive double filtration plasmapheresis (DFPP) as well as PE. No comparative trials between PE and DFPP, however, have been conducted. We compared their abilities to remove immunoglobulins and antiganglioside antibodies to find out whether DFPP is equivalent to PE. The ability to remove immunoglobulins and antiganglioside antibodies was compared between PE and DFPP using plasma samples from 41 patients with GBS and related diseases before and after each treatment session. The ability of DFPP to remove both IgGs and antiganglioside IgG antibodies were significantly inferior to those of PE. There is a less theoretical basis for selecting DFPP as the first choice of plasmapheresis for GBS and related disorders.     

Relapse of Graves' disease 23 years after treatment with radioactive iodine (131I)

The use of radioactive iodine (131I) in the treatment of Graves' disease results frequently in hypothyroidism requiring thyroid hormone supplementation. Relapse of Graves' disease months after inadequate treatment with 131I is well-recognized. However, late relapse of Graves' disease in a patient rendered hypothyroid by 131I years after therapy has not been reported. The authors discuss a patient who had a relapse of his Graves' disease 23 yr after treatment with 131I. Over the interval the patient had been on 1-thyroxine replacement for hypothyroidism and had persistently high levels of long acting thyroid stimulator or thyroid stimulating antibody. The authors speculate that the immune nature of Graves' disease may play a role in the observed clinical response to 131I.