CJASN ePress. Published on April 20, 2020 as doi: 10.2215/CJN.12501019

Therapeutic Plasma Exchange Using Membrane Plasma Separation

Sadiq Ahmed 1 and Andre Kaplan2

Abstract Therapeutic plasma exchange is a purification technique designed for the removal of large molecular weight toxins such as pathogenic antibodies and lipoproteins. Plasma exchange can be performed either by membrane 1Division of separation or centrifugation. Centrifugal plasma exchange is more common in the United States while Nephrology Bone and membrane separation is more popular in Germany and Japan. The membrane separation technique is similar to Mineral Metabolism, the ultrafiltration procedures performed with a standard dialysis machine but in which the membrane’s pores University of Kentucky, Lexington, are large enough to allow removal of all circulating molecules while retaining the cellular components. The Kentucky current availability of plasma separation membranes compatible with CRRT systems has dramatically increased 2Division of the potential for almost all nephrologists to perform these treatments. This review describes the membrane Nephrology, separation techniques available in the United States, the practical aspects of ordering and operating a membrane University of Connecticut Health separation plasma exchange procedure and its possible complications. Center, Farmington, CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.12501019 Connecticut

Correspondence: Introduction replacement by an equal volume of appropriate fluid Dr. Sadiq Ahmed, Therapeutic plasma exchange is a procedure carried Division of purify the blood by removing the pathogenic mole- Nephrology Bone and out for various life-threatening and debilitating cules responsible for certain diseases. The substances Mineral Metabolism, as a principal mode of treatment or as an adjunct with removed by plasma exchange are abnormally pro- University of other therapies. In this procedure, plasma is separated duced in the body in various diseased states. These Kentucky, 800 Rose from the cellular components of blood. The removed high molecular weight pathogenic molecules, such as Street, Room MN564, Lexington, KY 40536- plasma is discarded and replaced with a colloid, a Igs, proteins, or immune complexes (Table 1) (4,5), 0298. Email: Sadiq. combination of crystalloid and colloid (1), or fresh cannot be removed from the blood by conventional [email protected] frozen plasma. Separation of plasma from the cellular methods, such as dialysis or hemofiltration, due to components of blood can be achieved by two differ- their large size. Urgent removal of these molecules is ent techniques: either by membrane separation or by necessary to prevent ongoing organ damage because centrifugation. Plasma separation by centrifugation is these molecules have long half-lives; additionally, commonly performed by pathologists, transfusion therapies aimed at suppression of their production medicine experts, and nephrologists. Alternatively, take weeks or months to be effective. Rapid removal the concept of membrane separation of plasma using of these large molecules by plasma exchange reduces a filtration device is very similar to hemofiltration or morbidity and mortality. The commonly removed ultrafiltration using a dialysis machine and hence, molecules and their molecular weights are described mainly performed by nephrologists. Membrane fil- in Table 1 (4,5). tration plasma exchange is also referred to as mem- brane plasma separation. Although very popular in Japan and Germany (2), in the United States, the Mechanism of Plasma Separation by Membrane membrane separation technique, although gaining pop- Filtration Plasma Exchange ularity (3), is used less often compared with centrifugal Separation of plasma from the blood’s cellular com- plasma exchange. Nephrologists and dialysis nurses are ponents can be accomplished by filtration through a naturally familiar with this technique because they are highly permeable membrane. This methodology sepa- experts in using these machines. This review article will rates the blood into its cellular and noncellular compo- discuss the basic principles, mechanisms, instruments, nents by subjecting it to sieving through a membrane complications, and practical aspects of prescribing with pores that allow the plasma proteins to pass but therapeutic plasma exchange by membrane separation. retain the larger cellular elements within the blood path (Figure 1). Twenty-five years after the first centrifugal plasma exchange procedure in a patient with multiple Principles of Blood Purification by Membrane myeloma in 1952, the membrane separation technique Separation Plasma Exchange was introduced in 1978 (6,7) as an alternative to the The separation and removal of plasma from the patient existing centrifugal technique. Membrane separation by a semipermeable membrane and its simultaneous plasma exchange is very similar to the operation of a www.cjasn.org Vol 15 September, 2020 Copyright © 2020 by the American Society of Nephrology 1 2 CJASN

Table 1. Size and distribution of some of the proteins removed by therapeutic plasma exchange

Protein Concentration, mg/ml M.W. 3 103 D Percentage Intravascular

IgG (except IgG3 subclass) 12 150 45 IgG3 0.7 150 64 IgMa 0.9 950 78 IgA 2.5 160 42 IgD 0.02 175 75 IgE 0.0001 190 45 Albumin 45 66 44 C3 1.4 240 67 C4 0.5 200 66 Fibrinogen 3–434081 Factor VIII 0.1 100–340 71 Antithrombin III 0.2 56–58 45 Lipoprotein cholesterol 1.5–2.0 1300 .90

M.W., molecular weight. Modified from refs. 4 and 5, with permission.

conventional dialysis machine running in ultrafiltration contains all of the noncellular components of the patient’s mode (Figure 2) or a continuous RRT (CRRT) in venovenous plasma (Figure 1); as plasma is filtered out, it is replaced hemofiltration mode. In membrane separation plasma simultaneously with appropriate fluids (usually albumin exchange, instead of a regular filter designed for the or [FFP]) in equal volume to the removal of small and “middle” molecules, a special filter plasma removed to prevent hemodynamic compromise. with large pores (0.3–0.5 mm) is used. Pore sizes of these The removal rate of any given plasma component de- membranes are usually 0.5 mm or less, thus easily rejecting pends on the plasma filtration rate and its sieving co- the smallest cellular component, the (3 mm). Blood efficient (ratio of a given plasma protein or solute drawn from a central venous access, such as a dialysis concentration between the filtrate and the blood side of catheter, is passed through this special plasma filter before it the membrane). With the currently available modern is returned to the patient (Figure 2). Because of the large plasma filtration membranes, the sieving coefficient of pores, the ultrafiltrate or effluent produced in this manner even the largest molecules, weighing .1 million D (LDL

Figure 1. | Schematic section of a hollow fiber for plasma exchange. flows lengthwise along the interior of the fiber, whereas its plasma components, such as Igs, clotting factors, fibrinogen, and albumin, pass through the pores in the fiber wall and collect outside the fiber. The wall of the hollow fiber functions as the separating membrane with a pore size that allows penetration by plasma but not by the blood’s cellular components (red blood cells [RBCs], white blood cells [WBCs], and platelets). CJASN 15: ccc–ccc, September, 2020 Membrane Separation Plasma Exchange, Ahmed and Kaplan 3

purpose, but most are not available in the United States (2,8,9). Practitioners in the United States have only two choices of filters for membrane separation plasma exchange. They are the Prismaflex TPE-2000 plasma filter (Baxter) and the Plasmaflo OP-05W (Asahi Kasei Medical Company Ltd. Japan). The physical properties of these two filters are very similar but different from a conventional dialyzer, and they are compared in Table 2.

Efficacy of Membrane Separation in Comparison with Centrifugal Plasma Exchange Membrane separation is limited to plasma exchange only and cannot separate the cellular components of blood. For this reason, it cannot be used for cellular procedures, such as exchange, , removal, and harvesting stem fi Figure 2. | Blood flowing through the plasma filter, plasma separa- cells. The plasma exchanging ef ciency of membrane tion and infusion of replacement solution, and return to the patient. separation is similar to the centrifugal technique due to a very high (close to 100%) sieving coefficient(ratioofthe concentrations of the molecules between the filtrate and cholesterol, etc.), is essentially “one.” Thus, the concen- the blood) of the plasma proteins and the pathogenic tration of these larger proteins in the removed plasma molecules (10). Studies from the 1980s showed that flat- (effluent) is essentially equal to that in the patient’s plate parallel membranes had similar efficacy to centrif- circulating plasma. ugal plasma exchange (4). A recent prospective study compared membrane filtration by the Plasmaflo filter with the centrifugal separation by the Spectra Optia and found that both systems are equally effective in removing Igs Membrane Separation Plasma Exchange Options (Figure 3) (11); however, the centrifugal procedure required Available in the United States less time (11,12). In a retrospective study, membrane sepa- The flat parallel plate membrane (Centry TPE; Cobe) (8) ration was also found to be effective in the pediatric was the first membrane separation plasma exchange filter population (13). approved in the United States by the Food and Drug Administration in 1982, and it was found to be equally effective in removing plasma as centrifugal exchange (6). Kinetics of Ig Removal with Plasma Exchange Eventually, more advanced hollow fiber membranes The volume of plasma exchanged determines how evolved and replaced the parallel plates. Over the years, much of the pathogenic molecules is removed from the different types of plasma filters were marketed in the body. Removal of these molecules is independent of the United States, but most of those were discontinued. separationtechniqueused.Themembraneseparation Worldwide, there is a myriad of filters available for this procedure removes the pathogenic molecules from the

Table 2. Comparison of available membrane separation therapeutic plasma exchange filters in the United States with a dialyzer for hemodialysis

Specification TPE 2000 Filter Asahi Plasmaflo Filter F200NR Dialyzer

Indication for use Plasma exchange Plasma exchange Hemodialysis Molecular mass cutoff, D 3 million NA but estimated close to 3 million Estimated 15,000 Pore size, mm 0.5 0.3 NA Fiber material Polypropylene Polyethylene Polysulfone Hollow fibers Yes Yes Yes Surface area, m2 0.35 0.5 2 Blood volume in filter, ml 55 41 113 TMP, mm Hg 120–193 100 600 (maximum) Anticoagulation Heparin (citrate rare) Heparin (citrate rare) Heparin Blood flow rate, ml/min 100–250 Up to 200 Up to 600 Sieving coefficient Albumin 0.97 0.99 0 IgG 1 1 0 IgA 1 1 0 IgM 0.92 1 0 Sterilization Ethylene oxide g-Ray Ethylene oxide

NA, not available; TMP, transmembrane pressure. 4 CJASN

Figure 3. | Comparison between efficacy of membrane separation therapeutic plasma exchange (mTPE) and centrifugation therapeutic plasma exchange (cTPE). IgG and IgM levels before and after showing similar removal with the two techniques. Reprinted from ref. 11, with permission. intravascular space. The volume of distribution and the the pretreatment levels by 75% (15) (Figure 5). Exchange of t . 3 1/2 of the molecules have a role in its removal. For 1.5 estimated plasma volume during one single session t example, IgM is largely (78%) (14) intravascular with a 1/2 provides only minimal additional removal of these large of 5 days, and it can be removed effectively with a few molecules but increases the treatment time and cost. In a daily treatments. However, IgG is ,45% intravascular prospective trial (16) on patients with acute liver failure, t with a 1/2 of 21 days, and it needs more treatments with where antibody removal was not the focus, a higher volume reasonable intervals for effective reduction of its level. of exchange was found to be effective, but the potential toxins Intervals of 24–48 hours after each treatment will allow the involved with acute liver failure have a wide range of levels of the pathogenic target to increase due to new molecular weights; additionally, the plasma treatment was generation and equilibration between the extravascular supplemented with high-volume CRRT, which can be very and intravascular spaces (5) (Figure 4). Studies show that a effective in removal of small and middle molecular weight plasma exchange equal to 1 estimated plasma volume will toxins. Furthermore, in this study evaluating high-volume lower the pretreatment Ig levels approximately 63% and exchanges, the replacement fluid was FFP, and the higher that a 1.43 estimated plasma volume exchange will lower exchange volumes allowed for the infusion of larger vol- umes of coagulopathy-correcting FFP without risk of fluid overload (17).

Nephrology Consultations for Membrane Separation Plasma Exchange There are indications for plasma exchange for various dis- eases, including but not limited to the kidneys. The nephrology service is consulted by other services, such as - oncology, neurology, transplant medicine, and rheumatology, to perform plasma exchanges for various indications. The plasma exchange for nonkidney-related indications is planned together with the consulting services. This collaboration is essential for making sure that the indication for the procedure is valid, for placing appropriate vascular access, and for making decisions on the frequency and number of treatments for a particular patient. Over the last few years, the American Society for Apheresis has produced a detailed description Figure 4. | Progressive decline in IgG levels after three consecutive and evaluation of the varied indications for plasma plasma exchanges (1 plasma volume each). IgG increased between exchange. Their most recent set of guidelines was published treatments due to the combination of extravascular to intravascular re- in 2019 (18), and it is a valuable resource for nephrologists. equilibration and new IgG synthesis. Reprinted from ref. 5, with permission. The guideline is updated every 3 years and contains user- CJASN 15: ccc–ccc, September, 2020 Membrane Separation Plasma Exchange, Ahmed and Kaplan 5

Figure 5. | Relationship of plasma volume exchanged (Ve), estimated plasma volume (EPV), and percentage reduction in initial concentration 5 for pathogenic molecules removed during therapeutic plasma exchange. Ve/EPV 1(i.e., 1 plasmavolume will remove63% of the pretreatment 5 concentration of the molecule). Ve/EPV 1.4 or 1.4 plasma volume will remove 75% of the substance. Reprinted from ref. 15, with permission. friendly individual fact sheets for each where citrate exposure because higher volumes of blood are therapeutic plasma exchange has been considered as a processed in the membrane separation technique. Seventy treatment option. The most recent review provides 84 fact to eighty percent of the citrate infused in membrane sheets for 157 proposed indications (18). The fact sheet of a separation is retained by the patient due to reduced particular disease contains a brief review of pathogenesis, the removal because plasma extraction ratio is only rationale for plasma exchange, and a review of the relevant 20%–30% in membrane separation compared with 80% literature. The recommendations for plasma exchange for a in centrifugal exchanges. Citrate toxicity is still possible in particular disease are classified and graded. It also provides membrane separation even when heparin is used for technical notes on the volume of plasma to be exchanged per anticoagulation if FFP (contains 14% citrate by volume) treatment, the number and frequency of treatments, and the is used for replacement fluid in a patient with kidney or choice of replacement fluid for a particular indication. hepatic failure (23). Citrate-induced hypocalcemia can be avoided with prophylactic administration of calcium. A recent report of nearly 1000 membrane separation Access for Membrane Separation Plasma Exchange plasma exchanges with the NxStage machine found that A temporary or tunneled dialysis catheter is inserted in a only 7% of treatments required anticoagulation (3). central vein for membrane separation because other smaller-caliber central lines or peripheral accesses used for centrifugal exchange with low-blood flow rates are not Calculation of Plasma Volume compatible with the hemodialysis or CRRT machines for For the plasma exchange prescription, the patient’s membrane separation. A preexisting arteriovenous fistula plasma volume is estimated on the basis of the or graft can be used for membrane separation, and there are and weight of the patient in kilograms. A formula to cases where an arteriovenous fistula is created in certain estimate plasma volume is [0.0653 weight (kilograms)] 3 diseases requiring long-term plasma exchanges. It should [12 hematocrit] (24). This formula is simple, quick, and be noted, however, that the immediate removal of a large- reliable compared with other formulas (25–28). Plasma bore central venous catheter can cause bleeding after an exchange volume is usually prescribed as 1–1.53 estimated intensive run of plasma exchanges due to a substantial plasma volume. “depletion” coagulopathy (19,20).

Prescribing Replacement Solutions Anticoagulation for Membrane Separation Plasma Replacement fluid is infused into the patient during Exchange plasma exchange to prevent hemodynamic collapse. The Similar to hemodialysis treatments, unfractionated heparin replacement fluid replaces the lost volume and exerts is commonly used for systemic anticoagulation in membrane oncotic pressure to avoid . Replacement separation plasma exchange and given as a single bolus of choices are 5% albumin or FFP; 5% albumin is isosmotic, 3000–5000 IU or 40–60 U/kg (21) followed by 1000 IU/h as and its oncotic pressure is close to plasma (29). Many needed. Citrate (anticoagulant citrate dextrose-A solution) is centers use a combination of crystalloids and colloids, such commonly used in centrifugal exchange for anticoagulation, as normal saline for 25%–30% of the exchange volume at the but it is rarely used (22) in membrane separation due to beginning followed by 5% albumin for the rest of the higher risk of toxicity and hypocalcemia from increased procedure. Some centers add 50 g of 25% albumin to a liter 6 CJASN

of normal saline or Ringers lactate to get a final concentration pump, pressure monitoring system and the dialysis machine of 5% albumin for replacement solution. Increasing the saline is put on “isolated” ultrafiltration mode, which bypasses the infusion rate to 20% more than the plasma removal rate dialysate proportioning system. A dual-track PP O4A plasma can compensate for third spacing of saline (30). Albumin pump (supplied by Asahi Kasei) is attached to the tubing to derived from human plasma is highly purified with control the simultaneous plasma removal and replacement. negligible risk of allergic reaction, but albumin replace- Asahi stopped selling this pump in the United States ment does not compensate for the depletion of clotting market after 2017. factors. FFP replacement is mandated in certain diseases, In all of the above membrane filtration procedures, such as thrombotic thrombocytopenic purpura, to replace circuit pressure, TMP, and blood flow rates are kept low ADAMTS 13 (31) or if there is increased risk of bleeding (200 ml/min or lower) to avoid . because plasma exchange depletes the clotting factors. There is significant risk of anaphylactic reaction (20) with FFP, and this is the most serious complication of therapeutic Complications plasma exchange, with uncommon reports of death due to Electrolyte disturbances, depletion coagulopathy, access- – these reactions (32 34). The patients getting FFP should be associated complications (20), and reaction to FFP (anaphy- premedicated with intravenous diphenhydramine, and in- laxis, rigor, and hypotension) are some of the complications travenous steroid and subcutaneous epinephrine should be of this procedure. Use of the Plasmaflo OP-05W is kept ready at the bedside. associated with a potential for increased bradykinin levels, and it would be wise to discontinue angiotensin-converting enzyme inhibitors in any patient who is to be treated with Machine Settings fi this membrane (35). Symptomatic hypocalcemia is less In the United States, there are only two types of lters likely in membrane separation plasma exchange because available for membrane separation plasma exchange, and citrate is rarely used for anticoagulation, but it occurs they are used in three different settings as follows: more if FFP is used because it has citrate. Citrate in FFP can also lead to metabolic alkalosis with high-volume Prismaflex CRRT Machine with TPE-2000 Filter transfusion. Citrate toxicity is most likely to occur in a The Prismaflex CRRT machines are used by simply patient with hepatic or kidney failure (23) due to dimin- changing the CRRT cartridge to the TPE 2000 cartridge. ished citrate clearance. Hypomagnesemia and hypokale- The tubing and the filter are preattached and come as a mia can occur due to bulk removal and citrate binding singlekittosnapontothePrismaflex machine. This filter of magnesium because replacement fluid lacks these cannot be used with any other machine. The standard electrolytes. Muscle cramps can occur due to removal of blood flow rate for the procedure is usually 100–200 ml/min plasma from the vascular space. Thrombocytopenia is less (machine range allows 100–250 ml/min). The rate of common but can occur in membrane separation plasma plasma replacement and loss can be set as high as exchange, probably due to entrapment in the filter. In- 2000 ml/h (33 ml/min). The transmembrane pressure creasedriskofbleedingduetoremovalofclottingfactors (TMP) is maintained at 100 mm Hg or less. A faster removal and fibrinogen can occur with three or more exchanges per increases the filtration fraction and chance of clotting along week with albumin infusion. To prevent this, the last with increase of TMP and higher risk of hemolysis. A 3- to 4-L 500 ml can be replaced with FFP instead of 5% albumin exchange will take approximately 2 hours. The volume of (36). Close monitoring of complete blood counts, coagu- plasma removal in this system is calculated by a weighing lation status, and electrolytes (including magnesium scale in the machine. and ionized calcium) are necessary for patients undergo- ing plasma exchanges. Administration of medications, such as IgG and therapeutic antibodies (rituximab, etc.), NxStage System One with Plasmaflo OP-05W Filters The PlasmafloOP-05Wfilter is used with the NxStage should be scheduled after the plasma exchange to avoid System One machine and can also be used with other their removal. hemodialysis machines. For the NxStage System One machine, the NxStage supplies a plasma exchange cartridge. The cartridge comes with a Plasmaflo OP-05W filter and a Conclusions separate tubing set. The filter is manually attached to the Membrane-based plasma exchange technology is very tubing in the machine. The standard blood flow rate is similar to hemofiltration using an existing CRRT or dialysis 100–200 ml/min (machine range 10–200 ml/min). The plasma machine. Considering that nephrologists are experts in removal rate is also similar (i.e., up to 2000 ml/h; machine the use of extracorporeal blood purification therapies, maximum is 4000 ml/h), with a TMP goal of 100 mm Hg or membrane-based plasma exchange can be performed by less. In this system, volume of plasma is not measured by the the nephrology service with minimal additional training, weighing scale but by the number of pulse . thus making this valuable technique available to a greater number of their patients.

Hemodialysis Machine with Plasmaflo OP-05W Filter Disclosures fl fi The Plasma oOP-05W lter can also be used with a Dr. Ahmed and Dr. Kaplan have nothing to disclose. regular hemodialysis machine. The individual filters are sold by the Asahi Company. The filter is attached to a Funding regular hemodialysis machine and connected to the blood None. CJASN 15: ccc–ccc, September, 2020 Membrane Separation Plasma Exchange, Ahmed and Kaplan 7

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