Atsushi Ohkubo

Solute Removal Capacity of High Cut‐Off Membrane Plasma Separators

In vitro blood filtration was performed by a closed circuit using high cut‐off membrane plasma separators, EVACURE EC‐2A10 (EC‐2A) and EVACURE EC‐4A10 (EC‐4A). Samples were obtained from sampling sites before the plasma separator, after each plasma separator, and from the ultrafiltrate of each separator. The sieving coefficient (S.C.) of total protein (TP), albumin (Alb), IgG, interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), tumor necrosis factor‐α (TNF‐α), fibrinogen (Fib), antithrombin III (AT‐III), and coagulation factor XIII (FXIII) were calculated. The S.C. of each solute using EC‐2A and EC‐A4 were as follows; TP: 0.25 and 0.56, Alb: 0.32 and 0.73, IgG: 0.16 and 0.50, IL‐6:0.73 and 0.95, IL‐8:0.85 and 0.82, TNF‐α: 1.07 and 0.99, Fib: 0 and 0, FXIII: 0.07 and 0.17, respectively. When compared with the conventional type of membrane plasma separators, EVACURE could efficiently remove cytokines while retaining coagulation factors such as fibrinogen. Moreover, EC‐2A prevented protein loss, whereas EC‐4A could remove approximately 50% of IgG.

Removal Characteristics of Immunoglobulin G Subclasses by Conventional Plasma Exchange and Selective Plasma Exchange

Selective plasma exchange (SePE) using a selective membrane separator is a modified method of simple plasma exchange (PE). Immunoglobulin G (IgG) subclass distribution is one of the important immunological characteristics of IgG. However, there is little information regarding the removal characteristics of IgG subclasses by SePE and conventional PE. Here, we investigated the removal ratio of IgG subclasses by PE and SePE in seven patients with immunological disorders. When the mean processed volume was 0.88 plasma volume (PV) (corresponding to 2.12 L), the mean percent reductions by PE were as follows: IgG, 63.2%; IgG1, 64.5%; IgG2, 64.0%; IgG3, 61.4%; and IgG4, 69.5%. When the mean processed volume was 1.18 PV (corresponding to 2.98 L), the mean percent reductions by SePE were as follows: IgG, 51.6%; IgG1, 55.3%; IgG2, 52.0%; IgG3, 53.7%; and IgG4, 64.6%. In both PE and SePE, using albumin solution as the supplementary fluid, IgG was effectively eliminated regardless of IgG subclasses.

Removal Kinetics of Antibodies Against Glutamic Acid Decarboxylase by Various Plasmapheresis Modalities in the Treatment of Neurological Disorders

Plasmapheresis is one of the acute treatment modalities for neurological disorders associated with antibodies against glutamic acid decarboxylase (anti‐GAD). However, there is little information about the removal kinetics of anti‐GAD by various plasmapheresis modalities. Here, we investigated the removal rate of anti‐GAD and fibrinogen (Fib) by immunoadsorption (IA), plasma exchange using a conventional plasma separator (OP‐PE), and plasma exchange using a high cut‐off selective membrane plasma separator (EC‐PE) in two cases of anti‐GAD‐associated neurological diseases. In case 1, IA and OP‐PE were used, and the percent reductions were as follows: anti‐GAD: 38.2% and 69.1% and Fib: 67.7% and 68.2%, respectively. In case 2, OP‐PE and EC‐PE were used, and the percent reductions were as follows: anti‐GAD: 65.8% and 48.5% and Fib: 68.5% and 19.8%, respectively. OP‐PE could remove anti‐GAD more efficiently than IA. Further, EC‐PE could maintain coagulation factors such as Fib better than IA and OP‐PE. It is important to select the appropriate plasmapheresis modality on the basis of the removal kinetics.

Removal Characteristics of Immunoadsorption With the Immusorba TR-350 Column Using Conventional and Selective Plasma Separators.

In Japan, immunoadsorption (IA) is performed using a conventional plasma separator and Immusorba TR‐350 column (TR‐350) for the treatment of neurological immune diseases. By this method, TR‐350 has the limited maximal capacity of the immunoglobulin G (IgG) adsorption, and fibrinogen (Fbg) is reduced remarkably. Evacure EC‐4A10 (EC‐4A) is a selective plasma separator and the sieving coefficients of IgG and Fbg using EC‐4A were 0.5 and 0, respectively. Here, we investigated the removal characteristics of IgG and Fbg in IA by TR‐350 using two different plasma membrane separators: conventional plasma separator (PE‐IA) and EC‐4A (EC‐IA). In vitro filtration using plasma effluent was performed with a closed circuit. When the processed volume was 3 L, estimated removal amounts by PE‐IA were 3172 mg for IgG and 3329 mg for Fbg, respectively. When the processed volume was 3 L, estimated removal amounts by EC‐IA were 4946 mg and 1916 mg, respectively. EC‐IA can be considered useful for the removal of IgG, including auto‐antibodies, while retaining Fbg, thereby allowing even daily use.

Removal Dynamics of Immunoglobulin and Fibrinogen by Conventional Plasma Exchange, Selective Plasma Exchange, and a Combination of the Two.

While plasma exchange (PE) can eliminate plasma proteins, including all immunoglobulin (Ig) and coagulation factors, selective plasma exchange (SePE) can retain fibrinogen (Fbg). Here, we investigated the removal dynamics of Ig and Fbg in 53 patients with immunological disorders by PE, SePE, and a combination of the two. When the mean processed plasma volume (PPV) was 0.9 plasma volume (PV), the mean percent reductions of Ig and Fbg by PE were both approximately 62%–65%. When the mean PPV was 1.1 PV, the mean percent reductions by SePE were 53.1% for IgG, 30.1% for IgA, 3.6% for IgM, and 19.0% for Fbg, respectively. In the three plasmapheresis sessions performed on alternate days, we classified treatments into three categories: PE group (PE–PE–PE, N = 2), SePE group (SePE–SePE–SePE, N = 14), and PE/SePE group (PE–SePE–SePE, N = 4). The mean percent reductions of IgG, IgA, IgM, and Fbg were 82.0%, 80.4%, 87.3%, and 80.9%, respectively, for the PE group; 76.4%, 57.7%, 43.3%, and 35.9%, respectively, for the PE/SePE group; and 75.4%, 50.6%, 3.2%, and 29.3%, respectively, for the SePE group. Plasmapheresis modalities can be combined according to clinical conditions, for instance, to achieve both the unspecific removal of pathogens by PE and retention of coagulation factors, such as Fbg, by SePE.

Selective plasma exchange

Selective plasma exchange (SePE) is a new modality of simple plasma exchange that uses a selective membrane plasma separator Evacure EC-4A10 (EC-4A) (Kawasumi Laboratories Inc., Tokyo, Japan). EC-4A has a relatively small pore size of 0.03μm, which is around one-tenth that of conventional plasma separators. The sieving coefficients of albumin, immunoglobulin G (IgG), factor XIII (FXIII), and fibrinogen using EC-4A have been shown to be 0.73, 0.5, 0.17, and 0, respectively. Therefore, one session of SePE can remove approximately 50% of IgG regardless of the IgG subclasses while retaining coagulation factors, such as FXIII and fibrinogen. SePE may lower the risk of bleeding when compared with other plasmapheresis modalities. SePE cannot remove large molecular substances, including IgM. When only IgG is targeted by plasmapheresis, SePE is a useful and safe option. When various immunoglobulins are targeted by plasmapheresis, PE can be combined with SePE, which results in both the unspecific removal of pathogens by PE and the retention of coagulation factors by SePE. Careful selection of the modality is important, and when necessary, appropriate plasmapheresis modalities should be combined on the basis of the characteristics and removal kinetics of the pathogenic substances.

Selective Plasma Exchange for the Removal of Pemphigus Autoantibodies, Fibrinogen, and Factor XIII in Pemphigus Vulgaris

Pemphigus vulgaris is a serious autoimmune skin disorder associated with desmoglein 1 and 3. Selective plasma exchange (SePE) for pemphigus vulgaris remains unknown. We investigated the removal characteristics of pemphigus autoantibodies, immunoglobulins, and fibrinogen in three cases. When the mean processed volume for SePE was 1.2 plasma volumes, the mean percent reduction was 50.7% for desmoglein 1, 48.9% for desmoglein 3, 50.3% for IgG, 29.8% for IgA, 1.9% for IgM, and 17.6% for fibrinogen. In one case, the percent reduction after four sessions of SePE within eight days was 87.0% for desmoglein 1, 85.1% for desmoglein 3, 76.6% for IgG, 53.5% for IgA, 7.9% for IgM, 41.6% for fibrinogen, and 31.4% for factor XIII. SePE can effectively remove pemphigus autoantibodies and retain coagulation factors, e.g. factor XIII and fibrinogen. In severe cases, SePE can be useful and safe for induction therapy.

Removal Dynamics of Autoantibodies, Immunoglobulins, and Coagulation Factors by Selective Plasma Exchange on Three Consecutive Days: Removal Dynamics by Daily SePE

Selective plasma exchange has been shown to be effective in various diseases, but no studies have assessed the benefits of daily treatment. We aimed to investigate the removal dynamics of immunoglobulins, fibrinogen, and factor XIII on three consecutive days in three patients. For mean processed plasma volumes of 1.06 × plasma volume, reductions of 79.6%, 49.3%, and 8.6% were seen for immunoglobulins G, A, and M, respectively. The reductions for fibrinogen and factor XIII were 18.4% and 13.0%, respectively. Removal dynamics were similar for immunoglobulin G‐related autoantibodies and immunoglobulin G when using daily selective plasma exchange. Moreover, daily use effectively removed the immunoglobulin G while retaining the coagulation factors. When disease‐specific autoantibodies are limited to immunoglobulin G, daily selective plasma exchange may be a useful and safe method of intensive induction treatment for plasmapheresis. However, further study is required in larger cohorts to confirm these findings.

Immunoadsorption With a Tryptophan-Immobilized Column Using Conventional and Selective Plasma Separators in the Treatment of Myasthenia Gravis: Immunoadsorption with the Tryptophan-Immobilized Column Using Conventional and Selective Plasma Separators in the Treatment of Myasthenia Gravis

Dear Editor, Autoimmune neurological diseases are often treated by immunoadsorption (IA) using a conventional plasma separator and tryptophan-immobilized column (1). Recently, in vitro studies revealed that immunoadsorption by tryptophan-immobilized column using a selective plasma separator (SeIA) could eliminate IgG to a degree similar to that in IA while retaining fibrinogen (2,3). However, no previous reports have evaluated treatment with SeIA in clinical practice. Here we present a case of myasthenia gravis (MG) using IA and SeIA in the treatment. The patient was a 74-year-old male with MG diagnosed by clinical symptoms, physiological findings, and a positive reaction to antibodies against acetylcholine receptors (AChRAb). The patient developed an infection and was treated with antibiotics, which induced an acute exacerbation of MG resulting in hospital admission. The severity of MG did not improve with the administration of 10 mg oral prednisolone on alternating days following intravenous immunoglobulin (Ig) therapy, and the quantitative MG score changed from 13 to 15. The disease was finally controlled after a combination of 3 mg/day oral tacrolimus, 25 mg/day oral prednisolone, and six sessions of immunoadsorption using tryptophan-immobilized column (IA–SeIA–SeIA– SeIA–SeIA–IA) on alternating days. The score improved from 15 to 8, and the patient was discharged. IA was performed by Immusorba TR-350 column (IM-TR; Asahi Kasei Medical, Tokyo, Japan) using OP-05 W (Asahi Kasei Medical) as a conventional plasma separator, and SeIA was performed by IMTR using Evacure plus EC-4A10 (EC-4A; Kawasumi Laboratories) as a selective plasma separator (2,3). The sieving coefficients of IgG, factor XIII (FXIII), and fibrinogen using EC-4A were 0.5, 0.17, and 0, respectively (4). IM-TR has a high affinity to AChRAb and fibrinogen (1,2). We evaluated the reductions of AChRAb, IgG, fibrinogen, and FXIII after IA and SeIA. Figure 1 shows the percent reductions of these factors after one session of the following therapies: IA when the mean processed plasma volume (PPV) was approximately 1.9 L and SeIA when the PPV was 2 L. The removal rates for AChRAb were similar at approximately 45–47% after one session of IA and SeIA, whereas the removal rates for fibrinogen and FXIII in SeIA were lower than those in IA. This is the first report to investigate the reductions of AChRAb, IgG, FXIII, and fibrinogen by SeIA in clinical practice. SeIA could remove AChRAb to a degree similar to that by IA while retaining coagulation factors such as fibrinogen and FXIII. Furthermore, this is also the first report on the use of the combination of IA and SeIA in a patient with MG. Repeated IA can easily and significantly reduce fibrinogen, whereas SeIA can retain both fibrinogen and FXIII. SeIA can be a useful and safe modality of immunoadsorption when disease-specific autoantibodies are limited to IgG and IM-TR has a high affinity to these antibodies. Further studies are necessary to investigate the removal dynamics, therapeutic effects and complications of SeIA.

Fibrinogen Reduction During Selective Plasma Exchange due to Membrane Fouling

Fibrinogen is substantially reduced by most plasmapheresis modalities but retained in selective plasma exchange using Evacure EC‐4A10 (EC‐4A). Although EC‐4As fibrinogen sieving coefficient is 0, a session of selective plasma exchange reduced fibrinogen by approximately 19%. Here, we investigated sieving coefficient in five patients. When the mean processed plasma volume was 1.15 × plasma volume, the mean reduction of fibrinogen during selective plasma exchange was approximately 15%. Fibrinogen sieving coefficient was 0 when the processed plasma volume was 1.0 L, increasing to 0.07 when the processed plasma volume was 3.0 L, with a mean of 0.03 during selective plasma exchange. When fibrinogen sieving coefficient was 0, selective plasma exchange reduced fibrinogen by approximately 10%. Scanning electron microscopy images revealed internal fouling of EC‐4As hollow fiber membrane by substances such as fibrinogen fibrils. Thus, fibrinogen reduction by selective plasma exchange may be predominantly caused by membrane fouling rather than filtration.