The most common method for separating the plasma from the blood during a TPE procedure is centrifugation ( Fig. 65.2 ). Alternatively, TPE can be accomplished using a membrane filter and standard hemodialysis equipment. However, the centrifugal methods are more efficient. Potential disadvantages of membrane filtration include activation of complement and leukocytes by the artificial membrane and the need for a central catheter to obtain adequate blood flow rates. If severe kidney failure is present, and dialysis is required, the membrane filtration method can be done in combination with conventional hemodialysis. Both centrifugation and membrane filtration are safe and efficient TPE techniques; the main differences are the cost and expertise needed to operate.

Centrifugal separator for plasma exchange.

Blood is pumped into the separator container. As the centrifuge revolves, different blood components are separated into discrete layers, which can be harvested separately. Plasma is pumped out of the centrifuge into a collection chamber. Red blood cells, leukocytes, and platelets are returned to the donor, along with replacement fluid.

From Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange in kidney diseases. J Am Soc Nephrol. 1996;7:367–386.

The centrifugation method uses centrifugal force to separate whole blood into plasma and cellular fractions according to their density. The centrifugation process can be intermittent or continuous. The blood is pumped from the patient at a flow rate of up to 100 mL/min into the processing unit, which consists of a bell-shaped bowl that rotates at high speed. The denser cellular blood components are centrifuged against the lateral walls, and the plasma is removed through a central outlet on the top of the bowl. In intermittent centrifugation, a single needle can be used and each cycle removes about 500 to 700 mL of plasma; therefore the process needs to repeated five or six times to achieve the goal of 2.5 to 4.0 L (1–1.5 plasma volumes) and usually takes >4 hours. In the continuous flow centrifugation system, the blood is pumped continuously into a rapidly rotating bowl, where plasma and cells are separated. Plasma is removed at a specified rate, and the cells plus replacement fluid are returned to the patient in a continuous manner. This method is faster and is more suitable for hemodynamically unstable patients; however, it is more costly and requires two venipunctures or insertion of a dual-lumen central venous catheter.

TPE requires a reliable venous access. The clinical scenario, especially the possibility for long-term venous access, and the type of TPE being used are important factors to consider when deciding on peripheral or central venous access. A peripheral vein allows a maximum flow of up to about 50 to 90 mL/min, so a single venous access is adequate for intermittent centrifugation, whereas continuous centrifugation techniques will require two venous access sites. For short-term procedures, this may be adequate but loss of venous access from recurrent intravenous catheters and phlebotomy in chronically ill patients is a major problem. If a long-term TPE is planned (>1–2 weeks), then a central venous catheter is required, preferably one that is tunneled beneath the skin; this generally reduces the likelihood of infection and allows for better catheter performance. When the membrane filtration technique is used, a central venous catheter is necessary to sustain blood flows >70 mL/min. Central venous access can be achieved through the femoral, internal jugular, or subclavian vein; the femoral vein should be avoided if the treatment of the patient will be ambulatory. In patients who require lifelong therapy, such as LDL apheresis, either an arteriovenous (AV) fistula or AV graft should be considered.

Central venous catheters have numerous long-term complications, including catheter thrombosis, catheter infection, pneumothorax, central vein thrombosis, and vein stenosis. See Chapter 62 regarding the catheters used for maintenance hemodialysis.

To prevent clotting of the extracorporeal circuit, TPE requires anticoagulation. For centrifugation procedures, the acid-citrate-dextrose (ACD) solution (one-ninth the volume of solute/volume of solution), given as a continuous intravenous infusion, is the most frequently used anticoagulant. The infusion rate is adjusted according to the blood flow rate (target ratio ranges 1:10–1:25). When the venous flux and infusion rate of citrate are slow, there is an increased risk for catheter clotting. In this case, heparin (if not contraindicated) can be used alone or in combination with citrate.

For membrane filtration TPE procedures, the use of standard unfractionated heparin is preferred; the required dose of heparin is about twice that needed for hemodialysis because a significant amount of infused heparin is removed along with the plasma. However, heparin may enhance systemic anticoagulation more than expected because of the additional effect of dilution of clotting factors by the nonplasma replacement solutions. The initial loading dose of heparin (40 U/kg) is usually administered intravenously, followed by a continuous infusion (20 U/kg per hour) adjusted to maintain an adequate anticoagulation in the circuit. ^,

For patients who are receiving standard oral anticoagulation—warfarin or one of the direct-acting oral anticoagulants—additional low-dose anticoagulation with regional citrate or heparin should be added to facilitate the treatment and prevent clotting during the procedure. The heparin dose can usually be reduced by at least 50% in this situation. In critically ill patients with coagulation abnormalities, the use of regional citrate is recommended. Hirudin and lepirudin (thrombin inhibitors) are effective and relatively safe alternatives for patients with increased risk for thrombosis but have contraindications for heparin administration (e.g., heparin-induced thrombocytopenia and thrombosis). ^,

The choice of replacement fluids includes 5% albumin, fresh-frozen plasma (FFP) (or other plasma derivatives such as cryosupernatant), crystalloids (e.g., 0.9% saline and Ringer lactate), and synthetic plasma expanders (e.g., hydroxyethyl starch [HES]). Albumin is the most commonly used solution in TPE and is generally combined with 0.9% saline on a 50:50 basis. Albumin does not contain calcium or potassium and also lacks coagulation factors and immunoglobulins. It is safe and has never been associated with transmission of hepatitis or HIV. FFP contains complement and coagulation factors and is the replacement fluid of choice in patients with thrombocytopenic purpura (TTP) because the infusion of normal plasma may contribute to the replacement of the deficient plasma factor ADAMTS13. Plasma may also be preferable in patients at risk of bleeding (e.g., those with liver disease, disseminated intravascular coagulation, after a renal biopsy) or those requiring intensive therapy (e.g., daily exchanges for several weeks) because frequent replacements with albumin solution will eventually result in post-TPE coagulopathy and a net loss of immunoglobulins. The disadvantages of using FFP include the risk of viral disease transmission and citrate overload.

Colloidal starch has been used as a replacement solution. It is well tolerated, drug interaction is minimal, the potential for disease transmission is absent, and it is cost-effective when compared with human albumin. HES is a polysaccharide colloid used as an agent for plasma volume expansion and for enhancement of granulocyte yields during leukapheresis. Its pharmacology and safety have been well studied and, when used in moderate amounts in humans and animals, HES produces relatively minor changes in coagulation tests, and overt bleeding rarely occurs. In TPE procedures, the side effects of HES on coagulation factors and tests are comparable with those of other replacement fluids. HES can be safely used in the first two sessions of therapy in patients with an albumin level above 30 g/dL to perform short-term TPE; longer HES exposure (130 L within 20 months) can lead to symptomatic effects (e.g., sensory polyneuropathy and weight loss) and diffuse tissue infiltration with HES-laden foamy macrophages. Excessive HES exposure in patients with impaired renal function can result in acquired lysosomal storage disease, so HES should be avoided in chronic TPE procedures. Contraindications for using starches in TPE are congestive heart failure, renal or liver failure, coagulopathy, hyperviscosity, allergic reactions to starches, pregnancy, breastfeeding, and pediatric patients.

TPE is a well-tolerated and relatively safe procedure and, although adverse events are common, death is rare, occurring in <0.1% of all procedures. There are fewer adverse reactions when albumin is administered as volume replacement than when using FFP (1.4% vs. 20%). The high-risk criteria for adverse reactions associated with TPE are unstable vital signs, hypotension, active bleeding, severe bronchoconstriction, severe anemia, pregnancy, and conditions requiring continuous nursing support. Table e-65.1 summarizes the most common complications related to the procedure.

The Swedish registry of therapeutic apheresis has reported more than 14,000 procedures from 1996 to 1999; adverse events occurred in 4.2% of procedures, and no fatalities were reported. Of all the apheresis procedures, 1% had to be interrupted due to an adverse event. The most common adverse effects reported were paresthesias (0.52%), hypotension (0.5%), urticaria (0.34%), shivering, and nausea. Kiprov and associates, in another report of 17,940 procedures performed on 3583 patients, had an occurrence rate of adverse events in 3.9% of all procedures. The following adverse reactions were documented: reactions related to citrate toxicity (3%), vasovagal reactions and hypotension (0.5%), vascular access–related complications (0.15%), reactions related to FFP (0.12%), hepatitis B from FFP (0.06%), arrhythmias (0.01%), hemolysis due to inappropriate dilution of 25% albumin (0.01%), and one death (from underlying disease) during a TPE procedure (0.006%). No significant bleeding complications were observed, and patients receiving FFP had significantly higher rates of adverse reactions than patients receiving other exchange fluids. More recently, a retrospective cohort of 435 children treated with 1201 TPE procedures found 152 adverse events with pruritis/uriticaria in 7% and hypotension in 1.17%. One child developed disseminated cryptococciosis neoformans, three children developed toxic epidermal necrolysis, one had anaphylactic shock, but there were no deaths.

One of the most frequent complications of TPE is the hypocalcemia related to citrate infusion as an anticoagulant for the extracorporeal system or in the FFP administered as a replacement fluid. Citrate binds to free calcium to form soluble calcium citrate, thereby lowering the free but not the total serum calcium concentration. Hypocalcemia may manifest with perioral and distal extremity paresthesias. Symptoms can be prevented and reduced by administration of intravenous or oral calcium if the TPE therapy will last longer than 1 hour. The administration of oral calcium carbonate or addition of calcium gluconate to the return fluid is a useful maneuver to prevent hypocalcemia. The incidence of hypocalcemic symptoms is lowered with the prophylactic administration of calcium; without calcium prophylaxis, the incidence of symptoms was 9.1% (6 in 66 treatments), whereas with calcium prophylaxis the incidence was reduced to 1% (6 in 633 treatments). Marques and colleagues have reported an incidence of hypocalcemia of 3% when calcium gluconate is infused in 5% albumin.

Another complication of citrate administration is the development of metabolic alkalosis, but serum concentrations of bicarbonate higher than 35 mEq/L are rarely seen. Risk factors more frequently associated with this complication are use of FFP and low GFR (e.g., patients with TTP); this is because the excess of citrate generates bicarbonate, the excretion of which is limited by impaired kidney function. Replacement regimens using saline and albumin solutions can result in a 25% reduction in the plasma potassium concentration in the postapheresis period, which can be minimized by adding 4 mEq potassium/L to the replacement solution. Hypokalemia is also a consequence of metabolic alkalosis.

TPE can lead to a reduction in blood pressure that is usually due to a decrease in intravascular volume. Because the volume of extracorporeal whole blood is higher with intermittent centrifugation techniques, hypotension episodes are more common than with continuous modalities. Hypotension can also occur in response to complement-mediated reactions to the membrane filter or sensitivity to the ethylene oxide that is used to sterilize the membrane. Intravenous administration of FFP can rarely result in anaphylactoid reactions, themselves rarely resulting in death. FFP reactions are most often characterized by fever, rigors, urticaria, wheezing, and hypotension.

The development of dyspnea suggests the presence of pulmonary edema due to fluid overload; noncardiogenic edema can rarely occur as a component of anaphylactoid reactions. Rarely, massive pulmonary emboli can develop if the blood components that are reinfused are not adequately anticoagulated.

Plasma exchange with albumin replacement produces a predictable decrease in clotting factors that may predispose to bleeding (Table e-65.2). A single plasma volume exchange increases the prothrombin time by 30% and the partial thromboplastin time by 100%; these changes return toward normal within several hours, but with repeated TPE sessions, these abnormalities can persist. In reported studies, the most significant change is in the fibrinogen. Keller and colleagues have reported that fibrinogen levels decrease to 25% of pre-TPE levels and recover to baseline after 2 to 3 days. Therefore 1 L or more of FFP (3–4 U/L) should be substituted as the replacement fluid each week or sooner in patients at risk for bleeding. Thrombocytopenia is also a consequence of plasma removal, with larger volumes removed associated with greater platelet loss; the mean platelet reduction following a TPE procedure ranges from 9.4% to 52.6%. Clinical bleeding associated with TPE is rarely reported, and when TPE-related hemorrhage is present, it is more likely a consequence of thrombocytopenia or inadequate heparin neutralization. ^,

Removal of immunoglobulins and complement can result in immunodeficiency, which can exacerbate immunosuppressive effects of other therapeutic agents (e.g., corticosteroids, cyclophosphamide, and rituximab). However, in an RCT of TPE in patients with lupus nephritis, TTP, or multiple myeloma, patients receiving TPE were not more prone to infection than the other patients. Nevertheless, repeated apheresis treatments with albumin replacement will deplete the patient’s reserve of immunoglobulins for several weeks. If an infection occurs, a single infusion of intravenous immunoglobulin (IVIg) (100–400 mg/kg) will restore the plasma immunoglobulin concentration toward normal. Although estimates for the risk of viral transmission by the use of FFP are low, the large volumes from multiple donors increase the risk in patients receiving long-term TPE therapy. Use of large-volume plasma units collected from a single donor and the use of hepatitis B vaccine may reduce the risk of the patient acquiring a virally transmitted infection.

Substantial drug removal by TPE occurs for those drugs that are highly protein bound and therefore primarily limited to the vascular space. Among drugs used to treat kidney diseases, prednisone is not substantially removed, whereas cyclophosphamide and azathioprine are removed to some extent. This potential problem can be circumvented by administering the drug after a plasma exchange treatment.

Flushing, hypotension, abdominal cramping, and other gastrointestinal symptoms have been reported during TPE in patients receiving angiotensin-converting enzyme (ACE) inhibitors. In one report of 299 consecutive patients undergoing TPE, these atypical symptoms occurred in all 14 patients receiving an ACE inhibitor versus only 7% of those not treated with this medication. The administration of an ACE inhibitor may prolong the half-life of bradykinin, thus permitting the attainment of a clinically significant concentration in the plasma, so it is recommended to withhold this type of drug for 24 hours before TPE.

In summary, TPE is a relatively safe procedure, with most of complications being mild and reversible. However, moderate to severe reactions, even death, can occur, especially in patients with severe primary diseases.

The double-filtration plasmapheresis (DFPP; also called “cascade filtration”) is another variation of membrane plasmapheresis. In this technique, the plasma that has been separated by the membrane flows again through membranes with different pore diameters and filtration and adsorption characteristics, high-molecular-weight proteins are discarded, and low-molecular-weight substances, including valuable albumin, are returned to the patient. A small amount of substitution fluid, such as albumin, may be added.

In recent years, these basic techniques have been modified (such as high volume) and/or coupled to other separation modalities. Cytapheresis is the removal of leukocytes or platelets in hematologic conditions with hyperleukocytosis or thrombocytosis. Erythrocytapheresis (red blood cell exchange) can also be performed for sickle cell crisis; in this setting, the goal is the removal of more than 50% of hemoglobin S and replacement with normal allogenic red cells.

When the plasma filtration is carried out above a normal physiologic temperature, the process is called “thermofiltration.” This procedure is performed on patients with severe dyslipidemia, whereas cryofiltration is when the procedure is done with the temperature below normal and is used to remove immunoglobulin and immune complexes. Alternatively, plasma absorption and immunoabsorption procedures use affinity columns for processing the separated plasma. Adsorption columns, such as protein A columns, remove IgG antibodies and immune complexes; chemical affinity columns, such as dextran sulfate, have a negative charge and are used to remove antibodies or other positively charged plasma substances, such as LDLs and very-low-density lipoproteins (VLDLs). The Molecular Adsorbent Recirculating System (MARS) is a highly specialized combination of plasma separation, protein adsorption, and continuous dialysis used in some centers for treatment of acute liver failure (see Fig. 65.3 ).

Molecular Absorption Recirculating System (MARS).

MARS provides enhanced toxin removal by combining traditional removal of water-soluble toxins through conventional hemodialysis and albumin-bound toxins by linking an albumin circuit to remove protein-bound toxins. Blood is pumped from the patient into the MARS flux dialyzer that has a 10% to 20% albumin dialysate flowing countercurrent at ∼600 mL/min. The MARS dialyzer is porous for molecules up to 50kDa, so it restricts growth factors and albumin from freely crossing the membrane, but smaller protein-bound toxins filter through and the albumin dialysate has capacity to bind the filtered toxins. The albumin dialysate is then sequentially circulated through a charcoal filter and ion exchange resin before the “cleaned” albumin dialysate is returned to the patient. The standard continuous renal replacement therapy filter is used for ultrafiltration and removal of water-soluble toxins.

Anti–glomerular basement membrane (anti-GBM) disease is a disorder in which circulating antibodies are directed against the non–collagen (NC)-1 domain of the α ₃ chain of type IV collagen, resulting in RPGN. Goodpasture syndrome is classically defined by the triad of pulmonary hemorrhage, RPGN, and circulating anti-GBM antibodies. Table 65.3 summarizes renal outcome studies discussed later in patients with anti-GBM–mediated kidney failure.

The epidemiology of anti-GBM disease reveals that there may be seasonal variation and temporal clustering that suggest environmental factors may trigger disease in genetically susceptible individuals. Anti-GBM disease was associated with respiratory tract infections and prodromal fever in 140 patients in China. Smoking has also been linked to anti-GBM disease. Cigarette smoking and lung hemorrhage in glomerulonephritis caused by autoantibodies to the glomerular basement membrane increases the risk of patients presenting with pulmonary hemorrhage. These observations suggest that inflammation or damage to the alveoli alters the conformation of Col IV leading to subsequent antibody formation and subsequent antibody-mediated injury and alveolar hemorrhage. More than 90% of patients have circulating anti-GBM antibodies, and the titer of circulating antibodies correlates with disease activity. Approximately 60% to 70% of patients will have pulmonary disease in addition to RPGN and, rarely, a patient may present with pulmonary hemorrhage and no renal involvement.

Before the use of TPE and immunosuppression, the mortality rate exceeded 90%, with a mean survival time of <4 months. The use of TPE was introduced for the treatment of anti-GBM disease in 1975, in an adjunct manner with immunosuppressives. Immunosuppression and plasma-exchange in the treatment of Goodpasture syndrome has remained the prototype for treatment. Numerous uncontrolled studies and case series published thereafter have suggested the beneficial effect of TPE on overall survival and renal survival. The low incidence, sudden onset, and severity of disease have made it challenging to conduct RCTs. Currently, with the combination of TPE, corticosteroids, and cyclophosphamide, the mortality rate has been reduced to <20%. The role of TPE in anti-GBM disease involves the rapid removal of pathogenic antibodies, whereas cyclophosphamide is essential to reduce ongoing antibody production. The use of high-dose steroids targets the acute inflammation. A rapid reduction in anti-GBM antibody titers is necessary in view of the speed of glomerular damage, and this cannot efficiently be achieved by drug therapy alone.

Rapid initiation of treatment is critical because recovery of kidney function is much more likely in the early phase of disease before oliguria develops or dialysis is required. Albumin is the replacement fluid of choice, but fresh-frozen plasma (FFP) will be needed in patients with pulmonary hemorrhage or those who are at increased risk for bleeding. Long-term outcome of anti-GBM antibody disease treated with plasma exchange and immunosuppression was reported by Levy in an uncontrolled study, on the long-term outcomes in 71 patients with anti-GBM disease. All patients received a standard immunosuppressive regimen of oral prednisolone and oral cyclophosphamide plus TPE. Plasma exchange (50 mL/kg, to a maximum of 4 L) was performed by using a centrifugal cell separator daily for at least 14 days or until anti-GBM antibody was undetectable. Human albumin (5%) with added calcium and potassium was used as replacement fluid, and FFP (150–300 mL at the end of the exchange) was used in patients with recent surgery or renal biopsy and those with pulmonary hemorrhage. Overall patient survival was 81% at 1 year of follow-up (95% in those with a creatinine level <5.7 mg/dL and 65% in those who presented with dialysis-dependent renal failure). In patients who presented with a serum creatinine concentration >5.7 mg/dL (but did not require immediate dialysis), renal survival was 82% at 1 year and 69% at last follow-up. There was only 8% renal survival in patients presenting with dialysis-dependent kidney failure, and all patients who required immediate dialysis and had 100% crescents on kidney biopsy remained dialysis dependent. The conclusion was that all patients with anti-GBM antibody disease and severe kidney failure who do not require immediate dialysis should be treated with aggressive immunosuppression and intensive TPE. Because pulmonary hemorrhage is associated with high mortality, TPE should be initiated in patients with anti-GBM disease, regardless of the severity of the kidney failure.

A retrospective review of 221 patients with anti-GBM disease from a single center in China comparing corticosteroids alone and corticosteroids plus cyclophosphamide with corticosteroids plus cyclophosphamide and TPE found overall 72.7% patient survival and 25% renal survival at 1 year. The combination therapy of TPE plus corticosteroids and cyclophosphamide had an overall beneficial effect on patient survival (hazard ratio [HR] for mortality, 0.31 [0.16–0.63]; P = .001) and renal survival (HR for renal failure, 0.60 [0.37–0.96]; P = .032). In 96 patients with kidney-limited disease (no hemoptysis), the risk factors for end-stage kidney disease (ESKD) were oliguria or anuria (HR, 3.34; 95% confidence interval [CI], 2.03–5.50; P < .001), initial serum creatinine (doubling from 1.5 mg/dL; HR, 2.13; 95% CI, 1.65–2.76; P < .001), and the percentage of crescents (increased by 20%; HR, 1.83; 95% CI, 1.34–2.48; P < .001). Only the combination therapy of TPE plus corticosteroids and cyclophosphamide had a beneficial effect on renal survival (HR for renal failure, 0.41; 95% CI, 0.23–0.73; P = .002). Only 2 of 63 patients (3%) with presenting serum creatinine more than 6.8 mg/dL remained off dialysis at 1 year. Treatment with corticosteroids plus cyclophosphamide without plasmapheresis did not result in improved renal function ( P = 0.73). Several subsequent studies have had similar findings. ^, A more recent analysis found that renal survival was about 30% at 1 year.

To date, there has only been one small randomized trial in anti-GBM disease, which compared the addition of TPE to cyclophosphamide and corticosteroids on the clinical course of 17 patients with anti-GBM disease. Only two of eight patients who received TPE became dialysis dependent compared with six of nine in the immunosuppression-alone group, suggesting a trend toward better outcomes in the TPE group. Analysis of laboratory data and pathology showed the initial serum creatinine concentration and number of crescents were associated with better outcomes rather than therapeutics used. Patients with crescents <30% and preserved renal function did well in either arm of the study.

Immunoadsorption (IAS) is another modality of extracorporeal therapy that is currently being explored. IAS may be more efficient at clearing anti-GBM antibodies than is seen with plasma exchange. However, plasma exchange removes other factors that may have roles in inflammation and coagulation that could affect the response to treatment. A small study showed potential comparable outcomes of IAS to plasma exchange therapy. A newer study showed similar effectiveness for antibody reduction in patients with both anti-GBM and ANCA-associated kidney disease. These studies suggest that IAS could be considered in patients as an alternate therapy, but the lack of randomized studies and the unfamiliarity with IAS in most centers indicate that more study and experience are needed.

After kidney transplantation, allograft survival rates are comparable between patients with anti-GBM disease and those with ESKD due to other causes, although up to 50% may show linear immunoglobulin G (IgG) staining of the glomerular basement membrane. Comparable rates are only in context of kidney transplantations in patients with anti-GBM disease that have taken place only after maintenance of 6 to 12 months of seronegativity. On the other hand, transplantation in the presence of antibodies leads to disease recurrence in up to 50% of allografts. The immunosuppression used to prevent allograft rejection and the sustained disappearance of anti-GBM antibodies are thought to be the main reasons why recurrences in the allograft are rare. Overall, long-term patient and graft survival rates are excellent.

RPGN is characterized by rapid deterioration in kidney function occurring over a few days to a few weeks and, if untreated, can lead to ESKD. RPGN is characterized by severe inflammation and necrosis of most glomeruli and, frequently, by fibrocellular crescents (crescentic glomerulonephritis, GN). There are three major subgroups of RPGN: 1. anti-GBM disease and Goodpasture syndrome (discussed previously); 2. immune complex–mediated processes where there is immune deposition usually resulting from autoimmune diseases such as systemic lupus erythematosus (SLE), postinfectious processes, mixed cyroglobulinemia, and IgA nephropathy; and 3. pauci-immune diseases that are usually (∼80% of patients) associated with antineutrophil cytoplasmic antibodies (ANCA) including granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). There are limited data for the role of TPE in immune complex–mediated processes.

The rationale for using TPE in pauci-immune ANCA-associated diseases (e.g., GPA and MPA) was initially based on the similarity of the renal pathology of these disorders with anti-GBM disease, and some patients will have both anti-GBM and ANCA-related disease. Several small case reports have documented cases of dual-positive ANCA-associated vasculitis and anti-GBM disease; however, no standardized guidelines exist for managing this overlap syndrome. The documented cases generally follow treatment protocols similar to those for anti-GBM disease, incorporating TPE, corticosteroids, and immunosuppressive therapy to target both antibody-mediated and inflammatory components of the disease.The first use of TPE for the treatment of RPGN associated with GPA was reported in 1977 when the combination of plasmapheresis, oral prednisolone, and cyclophosphamide was associated with rapid recovery of kidney function in five of nine patients. However, several studies throughout the 1990s did not demonstrate an additional benefit for the use of TPE in the treatment of ANCA-associated diseases. For example, Hammersmith Hospital reported a controlled trial of TPE in focal necrotizing glomerulonephritis on 48 patients randomized to conventional treatment with oral steroids, cyclophosphamide followed by azathioprine, with or without intensive TPE (at least five exchanges in the first 7 days). There was no benefit in patients with moderate or severe kidney disease who were not dialysis dependent at presentation. However, this study was the first to suggest that some patients who were dialysis dependent may be able to discontinue dialysis after treatments that included TPE (10/17 in the TPE group vs. 3/8 in the conventional group).

The Canadian Apheresis Study Group randomized 32 patients with RPGN to receive intravenous methylprednisolone, followed by oral prednisolone, and azathioprine with or without TPE (10 exchanges in the first 16 days). Again, there was no demonstrable benefit of TPE in non–dialysis-dependent patients; however, three of four dialysis-dependent patients who received TPE were able to come off dialysis compared with only two of seven patients who did not receive TPE.

In one of the largest studies, Jayne and colleagues reported on 137 patients with ANCA-associated systemic vasculitis confirmed by kidney biopsy and serum creatinine concentrations higher than 5.7 mg/dL. Patients were randomized to receive seven TPE procedures ( n = 70) or 3 g of methylprednisolone in divided doses ( n = 67). Both groups received oral cyclophosphamide and oral prednisolone as maintenance therapy. Dialysis independence at 3 months was the primary endpoint, and 33/67 (49%) of methylprednisolone-treated patients were alive and independent of dialysis compared with 48/70 (69%) of patients who received TPE ( P =.02). When compared with methylprednisolone, TPE was associated with a 24% reduction in risk of progression to ESKD at 1 year.

A meta-analysis has supported the concept that TPE may reduce dialysis dependence, although there was no benefit on survival. RCTs for treating renal vasculitis were included in the analysis (31 trials), and 8 included adjuvant plasma exchange. At 12 months, there was a significant reduction in the need for dialysis in 6 trials with 235 patients (relative risk, 0.45; 95% CI, 0.29–0.72); the number needed to treat was 4 to 10. However, the PEXIVAS trial randomized 704 patients with eGFR<50 mL/min or pulmonary hemorrhage to 7 TPE sessions within 14 days. All patients received cyclophosphamide or rituximab and pulse steroids. Although confidence intervals were wide, there was no benefit to receiving TPE on overall or renal survival at 1 year. In conclusion, although study sizes are relatively small, presentations vary in disease severity and the provision of TPE cannot be blinded. Available data in aggregate support a beneficial role for TPE in the treatment of patients with ANCA-associated vasculitis and severe kidney disease (sCr >500 μmol or 5.7 mg/dL) at presentation or with relapsing disease. In patients with ANCA- and anti-GBM–associated disease presenting with diffuse pulmonary alveolar hemorrhage, TPE may be beneficial for pulmonary recovery and reduction of risk of progression to dialysis. Therefore TPE is, at present, the best adjunct to immunosuppressive therapy for patients with advanced kidney disease from these mechanisms of injury. Nevertheless, the use of TPE for less severe kidney disease is still not clear.

Acute and chronic kidney disease (CKD) are common and potentially serious complications of SLE. Management of patients with active lupus nephritis (LN) comprises an induction treatment, followed by long-term maintenance therapy. The mainstay of LN treatment has been based on the use of corticosteroids plus cyclophosphamide (IVC) or mycophenolate in patients with active disease. Rituximab has been considered as an alternative in the treatment of proliferative LN, but data from a randomized controlled study suggested no additional benefits when looking at outcomes of remission with rituximab and mycophenolate versus mycophenolate alone. Newer therapies including voclosporine and belimumab have efficacy in LN, but none have been studied in combination with TPE.

The use of TPE for patients with SLE was first reported in the 1970s where removal of high levels of circulating immune complexes showed clinical improvement. However, it was not until the results of the Lupus Nephritis Collaborative Study Group in 1992 that there was a randomized study to examine the safety and efficacy of TPE systematically. The Lupus Nephritis Collaborative Study Group was a large, randomized, controlled multicenter trial comparing a standard therapy regimen of prednisone and cyclophosphamide with a regimen of standard therapy plus TPE in patients with severe LN. In this study, 46 patients were randomized to the standard therapy group and 40 were randomized to the TPE group. Histologic categories included LN types III, IV, and V. TPE was carried out three times per week for 4 weeks, and drug therapy was standardized. The mean follow-up was 136 weeks and, although patients treated with TPE experienced more rapid reduction of antibodies to double-stranded DNA and cryoglobulins, the addition of TPE did not improve clinical outcomes. Kidney failure developed in 8 of 46 patients (17%) in the standard therapy group compared with 10 of 40 patients (25%) in the TPE group, and 6 of 46 (13%) died in the standard therapy group compared with 8 of 40 (20%) in the TPE group. Results were similar in magnitude and direction after an extended follow-up of 277 weeks.

Other small trials have had similar negative results, while some studies have suggested benefit. TPE and pulse intravenous cyclophosphamide, followed by oral cyclophosphamide and prednisone, were trialed in an uncontrolled study of 14 patients with severe lupus. All 14 patients responded, and 8 remained off therapy for 5 to 6 years. One patient had a major relapse, and two others had a minor relapse at 2 and 3 years. The main adverse effect was herpes zoster; in addition, 4 of 14 women developed irreversible amenorrhea. Danieli and colleagues compared two groups of patients with proliferative LN at 4 years of follow-up. Group I (12 patients) received synchronized therapy with TPE and cyclophosphamide, whereas group II (16 patients) received intermittent cycles of cyclophosphamide. At the end of the follow-up, the patients who received synchronized therapy had a faster remission than the other group, but renal outcomes were not superior to conventional therapy at long-term follow-up.

Although the current literature does not support a clear benefit for the addition of TPE to immunosuppressive therapy for LN, it may be considered for select patients with severe disease and no response to conventional treatment. IAS may be the preferred option, compared with PE, due to safety profiles. As a result, the American Society for Apheresis does not consider TPE for LN but TPE should be considered in patients with catastrophic antiphospholipid antibody syndrome in patients with lupus or refractory severe disease (category II; 2C).

The first time that cryoglobulinemia was identified in the blood of a patient with multiple myeloma, where it was noted that cooling of the patient’s blood resulted in a precipitate forming which disappeared upon subsequent heating, was 1933. Cryoglobulinemia refers to the presence of serum proteins that precipitate at temperatures below 37°C and redissolve on rewarming. When purified, they can be categorized into three main groups: monoclonal (type I cryoglobulinemia), mixed monoclonal and polyclonal (type II cryoglobulinemia), and polyclonal IgG and IgM (type III cryoglobulinemia). The immunochemical composition of cryoglobulins often correlates phenotypically with clinical symptomology of disease. More than 80% of patients with mixed cryoglobulinemia are infected with hepatitis C virus (HCV), although cryoglobulinemia can also be seen in plasma cell dyscrasias and with vasculitis. The glomerular injury is the consequence of glomerular deposition of immune complexes, and the kidney’s manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome, with variable progression toward ESKD. ^, There have been no randomized, controlled studies of TPE for cryoglobulinemia; however, the removal of pathogenic cryoglobulins is rational, and there have been numerous anecdotal case reports and uncontrolled studies showing that TPE may benefit patients with severe clinical manifestations of cryoglobulinemia such as progressive kidney failure, severe or malignant hypertension, purpura, and advanced neuropathy. ^, Uncontrolled studies with more than five patients have shown that TPE induces rapid reduction in the “cryocrit” (the proportion of plasma comprised of cryoglobulin), improved kidney function in 55% to 87% of patients, and improved survival (∼25% mortality rate) compared with historical data (∼55% mortality rate). Plasma exchange does not prevent the formation of new cryoglobulins or treat the underlying disease, and rebound production can occur after cessation of TPE without therapy directed at the cryoglobulin-producing B cell clones or treatment of the underlying disease process. The unique characteristics of cryoglobulins have led to modifications of the TPE technique to enhance their removal. Cryofiltration is a modified technique that reduces circulating levels of cryoproteins. In this technique, the plasma is cooled in the extracorporeal circuit to precipitate the proteins, allowing a more efficient removal of the pathogenic proteins.

In a multicenter retrospective study that included 159 patients with cryoglobulinemia, including 113 HCV‐positive patients, it was shown that the TPE led to complete remission in 12% of cases, partial remission in 38% of cases, transient remission in 25% of cases, and no remission in 22% of cases. The treatment of hepatitis C has been revolutionized with the introduction of direct antiviral agents, but few data are available on the safety and efficacy of antiviral therapy with direct-acting antivirals in the treatment of HCV-related cryoglobulinemia. Some trials have shown that patients treated with sofosbuvir-based, direct-acting antiviral therapy experience improvement in kidney function.

Although therapies for type I and type II cryoglobulinemia (such as immunosuppression, antivirals, or chemotherapy) are quite effective, they take time to work. Given that cryoglobulins can affect multiple organs, use of different modalities of apheresis can be an effective way to rapidly decrease these serum proteins, providing time for other therapies to take effect.

The American Society of Apheresis classified severe/symptomatic cryoglobulinemia a category 2, meaning it is reasonable to use apheresis as a second‐line therapy using either plasmapheresis (grade 2A) or immunoadsorption (IA; grade 2B).

Kidney injury is a common finding in MM, affecting 20% to 50% of patients at diagnosis, and 10% to 15% will develop ESKD. Kidney injury can be caused by a variety of factors, including precipitation of myeloma light chains in renal tubules (Bence Jones proteins) that can lead to direct tubular toxicity (cast nephropathy). In addition, paraproteins can cause numerous other pathologic patterns of injury, including MPGN, C3 nephropathy, and light and heavy chain deposition disease and can be associated with rare forms of glomerulonephritis such as fibrillary and immunotactoid glomerulonephritis. Other factors frequently implicated in MM-associated kidney failure include hypercalcemia, hyperuricemia, amyloidosis, hyperviscosity, infections, and chemotherapeutic agents. A kidney biopsy is needed to establish the mechanism of injury but may not be obtained if the MM is being treated. This has confounded studies on the role of TPE.

Given the high association of kidney disease in MM, it is important to identify the diagnosis early to improve renal outcomes (CKD and ESRD). Before use of modern chemotherapeutic methods, patients with AKI and MM on dialysis had <25% chance of renal recovery. Currently, the combination of the proteasome inhibitor bortezomib with dexamethasone is the standard regimen in newly diagnosed patients and has shown to suppress light chain production. The rationale to use TPE in MM is with the goal to decrease light chains levels quickly (as the literature shows lower light chain levels are associated with improved renal outcomes and survival). In 2018, Premuzic and colleagues published a study of 29 patients with MM and AKI who underwent treatment with bortezomib or bortezomib and plasmapheresis); the pheresis group showed a more pronounced significant reduction in light chain level (serum free light chains decreased from 2422 mg/L to 34 mg/L in the TPE arm vs. a decrease from 2248 mg/L to 182 mg/L in the bortezomib-alone arm). There was also a correlation of better outcomes with higher number of sessions of TPE. However, there have been a few RCTs where TPE was not shown to reduce adeverse renal outcomes or death. However, this was a relatively small study of 104 patients with AKI at the onset of myeloma. Importantly, a kidney biopsy was not needed for inclusion, so it is unclear whether a subset of patients had benefit.

TPE only removes 25% of light chain volume in 3 weeks, so this has prompted an exploration of newer methods of light chain removal by modifying aspects of the hemodialysis procedure. Most (90% of) light chains could be removed by high-cutoff dialysis membranes (HCO-HD) with extended dialysis times in 3 weeks. Changing dialyzers during extended HD and increasing UF rates were also shown to be associated with light chain removal rates. Newer studies have shown increased light chain removal with the use of HCO-HD. ^, Most of these studies were retrospective and adjustments for baseline eGFR status, percentage of plasma cells, renal biopsy findings, etc. were not consistently reported.

A small retrospective study looked at AKI, specifically in MM, and compared the use of chemotherapy alone versus chemotherapy along with CVVH and hemoperfusion. After 1-year follow-up, the improvement in renal function was significant in the chemotherapy with CVVH and hemoperfusion combination group. This group had 14 complete remissions and 19 partial remissions compared with 9 complete remissions and 11 partial remissions in the chemotherapy-alone group, a statistically significant result. Another approach has been to use multiple polymethylmethacrylate membrane filters in the course of the dialysis treatment. This is based on the observation that free light chains bind to and saturate the membrane filter. In one study on patients presenting with AKI and MM requiring HD, the use of two polymethylmethacrylate membranes along with bortezomib allowed reduction of FLC to <200 mg/L. Close to 70% of patients showed renal recovery in 60 days.

In aggregate, these studies leave the role of TPE and modified dialysis techniques in the management of myeloma-associated kidney injury unresolved. Questions remain about subgroups of patients who may benefit, and individuals should be assessed on a case-by-case basis while larger studies are needed.

Waldenström macroglobulinemia (WM) is a B cell disorder resulting from the accumulation of clonally related IgM-secreting lymphoplasmacytic cells. The morbidity associated with WM is typically mediated by tissue infiltration by neoplastic cells and by the physicochemical and immunologic properties of the monoclonal IgM. In patients with symptomatic hyperviscosity, cryoglobulinemia, or moderate to severe cytopenias, emphasis should be placed on achieving rapid reduction in the burden of plasma paraproteins. This was demonstrated in a study where 95 patients with symptomatic hyperviscosity (81%) received plasma exchange as the initial therapy, while 23 were treated with chemotherapy alone. Following plasma exchange, 90% of patients experienced a resolution of hyperviscosity-related symptoms. The median reduction in serum IgM and serum viscosity after plasma exchange during the first episode was 2860 mg/dL, with a range from 260 to 9900 mg/dL. In these circumstances, TPE of one or two sessions was effective in reducing serum IgM levels. Treatment should be initiated as soon as possible, with a regimen including bortezomib, dexamethasone, and rituximab to achieve more rapid disease control.

TPE has been widely used in hematologic and oncologic diseases; however, only the following disorders are considered category I by the American Society for Apheresis: 1. TTP (discussed later); 2. polycythemia vera with severe erythrocytosis; 3. sickle cell disease (red cell exchange); 4. hyperviscosity in hypergammaglobulinemias; and 5. cutaneous T-cell lymphoma (photopheresis).

The thrombotic microangiopathies (TMAs) are multisystem disorders that can affect children and adults, may be hereditary or acquired, and share a spectrum of abnormalities in numerous organ systems. The hallmark clinical features of this syndrome include microangiopathic hemolytic anemia, thrombocytopenia, and organ (including kidney) injury. The pathologic features are vascular damage manifested by arteriolar and capillary thrombosis. Common causes of this syndrome include toxins from bacteria or drugs, abnormal complement activation that can be genetic or autoantibody-induced, production of procoagulant factors (antiphospholipid antibodies), loss of anticoagulants (defects on ADAMTS13), and severe hypertension. ^, According to the latest ASFA guidelines, the TMA diseases with class I recommendation for TPE procedures are thrombotic TTP, complement-mediated TMA when it is associated with factor H antibodies, and ticlopidine-associated TMA.

TTP, also known as TMA-ADAMTS13 deficiency, is a systemic thrombotic illness affecting mostly small vessels. Presenting clinical features of acquired TTP are weakness, gastrointestinal symptoms, purpura, and transient focal neurologic abnormalities. Clinical presentation is diverse because some patients have minimal abnormalities, whereas others are critically ill. Diagnostic criteria are the presence of microangiopathic hemolytic anemia and thrombocytopenia without another apparent cause; an ADAMTS13 level of <10% of normal activity supports the clinical diagnosis of acquired TTP. ^, Multimers of von Willebrand factor (VWF) normally accumulate on the endothelial cell membrane and are rapidly cleaved into normal-sized multimers by the ADAMTS13 protease. TTP results from the accumulation of unusually large VWF (ULVWF) due to insufficient ADAMTS13 activity. The accumulation of UVWF multimers results in platelet microthrombi formation and subsequent microangiopathic hemolytic anemia. An inhibitory autoantibody to the ADAMTS13 metalloproteinase has been found at varying titers among a high percentage of patients with the idiopathic form of this disease.

Before the introduction of plasma infusion and TPE, the disease rapidly progressed and was almost uniformly fatal (90% mortality). In 1977, it was discovered that infusion of FFP or TPE with FFP replacement was able to reverse the course of disease. ^, The PLASMIC score is a clinical tool used to assess the probability of TTP in patients with TMA while awaiting ADAMTS13 test results. It consists of seven components, and patients are awarded 1 point for each laboratory parameter, including the following:

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  Platelet count (<30,000/mm )

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  Hemolysis evidence (indirect bilirubin >2 mg/dL or LDH >2× ULN)

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  Absence of active cancer (1 point if no active cancer)

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  No solid organ or stem cell transplant history (1 point if no such history)

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  Mean corpuscular volume (MCV) (<90 fL)

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  International normalized ratio (INR) (<1.5)

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  Creatinine level (<2 mg/dL)

A review and meta-analysis looked at how well the PLASMIC score predicts TTP in patients, using data from 13 studies with 970 patients. TTP was present in 35% of cases. A PLASMIC score of 5 or higher had a sensitivity of 99% and a specificity of 57%. Scores of 6 or higher lowered sensitivity to 85% but increased specificity to 89%. These results suggest that patients with a score of 5 or more should be treated for TTP unless another clear diagnosis explains their symptoms without waiting for confirmation of the ADAMSTS13 assay.

Currently, daily TPE is the mainstay treatment by removing the inhibitory autoantibody and repletion ADAMTS13 with FFP. Plasma exchange with FFP is more effective than plasma infusion alone; at 6 months, the remission rate is 78% versus 31%, and the survival rate with these two procedures is 78% versus 50%. If there is a delay in initiating TPE, large-volume plasma infusions are indicated as initial therapy. The optimal duration of TPE is not known but, in TTP, TPE is performed daily until the platelet count has risen to near-normal and evidence for hemolysis (schistocytes, lactate dehydrogenase [LDH] elevation) has resolved. There is a wide range of reported exchanges (3–145), with an average of 7 to 16 daily exchanges necessary to induce remission. ^, The ASFA guidelines recommend daily TPE until the platelet count is above 150,000/L for 2 or 3 consecutive days and the LDH level is close to normal.

When present, neurologic symptoms usually improve rapidly, and the serum LDH level tends to improve over the first 1 to 3 days. Improvement in the platelet count may not be seen for several days, however, and improvements in kidney function often take longer. Patients requiring dialysis at presentation may be able to recover enough function to discontinue dialysis, but many patients have residual CKD. When a normal platelet count has been achieved, plasma exchange is gradually tapered by increasing the interval between treatments. Many patients (one-third to one-half) will abruptly develop recurrent thrombocytopenia and increased evidence of hemolysis when daily plasma exchanges are tapered or stopped. Some of these patients may benefit from the addition of prednisone or other immunosuppressive therapy (e.g., cyclosporine and rituximab), although there are sparse data evaluating the safety, efficacy, and effectiveness of these agents.

Although there is no evidence for a beneficial role of TPE in patients with hemolytic uremic syndrome (HUS), TTP is often secondary to drugs, including cancer chemotherapy and calcineurin inhibitors or when associated with bone marrow transplantation. There is a single uncontrolled report of 60 patients with ticlopidine-associated TMA, suggesting that TPE enhances survival (50% vs. 24% mortality). One well-defined cause of HUS (now called TMA–Shiga toxin-mediated) is the syndrome associated with hemorrhagic diarrhea caused by Escherichia coli O157:H7. In this disease, the enterotoxin induces colonic vascular injury, leading to systemic absorption and activation of numerous pathways, causing endothelial cell damage over several days. Platelet microthrombi are particularly prominent in the glomerular capillaries and often lead to severe AKI. Supportive care with fluid resuscitation and timely renal replacement therapy is the mainstay of therapy, glucocorticoids are not indicated, and there is no compelling evidence from the literature that TPE benefits patients with this syndrome. However, patients with severe bloody diarrhea or neurologic involvement may respond to TPE. During the 2011 outbreak in Germany, TPE was carried out in 87% patients, yet evidence of benefit was not seen, and improvement in general medical care rather than the frequent and early use of TPE was the potential explanation of the better outcome in comparison with historic controls. A group of patients with more severe disease received TPE plus eculizumab, but survival was not enhanced with addition of this agent.