Given their expertise in vascular access, anticoagulation, volume management, and solute clearance, nephrologists are well suited to manage all methods of blood purification, including therapeutic plasma exchange (TPE). This core curriculum is an annotated primer and bibliography for understanding the indications, technique, and complications associated with TPE.

Introduction and Rationale

TPE is an extracorporeal blood purification technique designed for the removal of large-molecular-weight substances. Examples of these substances include pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxin, and cholesterol-containing lipoproteins.

For TPE to be a rational choice as a blood purification technique, at least 1 of the following conditions should be met: (1) the substance to be removed is sufficiently large (≥15,000 d) to make other less expensive purification techniques unacceptably inefficient (ie, hemofiltration or high-flux dialysis), (2) the substance to be removed has a comparatively prolonged half-life so that extracorporeal removal provides a therapeutically useful period of diminished serum concentration, and (3) the substance to be removed is acutely toxic and resistant to conventional therapy so that the rapidity of extracorporeal removal is clinically indicated.

The removal of pathogenic autoantibodies offers an example. If one considers that the natural half-life of immunoglobulin G (IgG) is approximately 21 days and assuming that an immunosuppressive agent could immediately halt production (unlikely), serum levels would still be 50% of the initial values for at least 21 days after initiating therapy. Such a delay might be unacceptable in the presence of a very aggressive autoantibody, such as that involved with Goodpasture syndrome.

Introduction and Rationale: Suggested Readings

Cohen S, Freeman T: Metabolic heterogeneity of human gamma globulin. Biochem J 76:475-487, 1960

Indications

In 1985, the American Medical Association (AMA) Council on Scientific Affairs convened a panel of 10 experts to review the available data for the efficacy of plasma exchange. Their assessment assigned each potential indication into 1 of 4 categories:

I.Standard therapy, acceptable but not mandatory

II.Available evidence tends to favor efficacy: conventional therapy usually tried first

III.Inadequately tested at this time

IV.No demonstrated value in controlled trials

Since this AMA review, there have been several well-designed randomized controlled trials that added significant new insight into the proper application of TPE. In consideration of these new studies, 2 subsequent reviews have attempted to update the original AMA recommendations. Added to these updated reviews is an assessment by the American Academy of Neurology. Most recently, in June 2007, the American Society for Apheresis published their exhaustive review of the indications for plasma exchange and the most current assessment of the available supportive evidence. The rating system of this most-up-to-date review uses categories (I to IV) similar to the previous reviews.

The original AMA indications, updated and modified by the 4 subsequent reviews, are listed in Table 1.

Table 1.

Indications for TPE


Reference	1	2	3	4	5
Year	1986	1993	1994	1996	2007
	Rating	Rating	Rating	Rating	Rating
Neurological diseases
Guillain-Barre syndrome	I	I	I	est	I
Myasthenia gravis	I	I	I	est	I
Chronic inflammatory demyelinating polyneuropathy	III	I	I	est	I
Paraprotein-associated polyneuropathy	nl	II	nl	est	I-III
Multiple sclerosis	II	III	III	pos	II-III
Eaton Lambert syndrome	nl	I	nl	pos	II
Stiff man syndrome	nl	nl	nl	invest	III
Amyotrophic lateral sclerosis	IV	IV	IV	nl	nl
Neuromyotonia	nl	nl	nl	invest	nl
Acute disseminated encephalomyelitis	nl	nl	nl	invest	III
Refsum's disease	nl	I	nl	invest	II
Sensorineural hearing loss	nl	nl	nl	nl	nl
Hematologic disorders
Hyperviscosity syndrome	I	I	I		I
Cryoglobulinemia	II	I	I		I
Thrombotic thrombocytopenic purpura	I	I	I		I
Hemolytic uremic syndrome	nl	II	II		III-IV
Idiopathic thrombocytopenic purpura	III	III	III		II-IV
Posttransfusion purpura	II	I	I		III
Autoimmune hemolytic anemia	III	III	III		III
Maternal-fetal incompatibility-Rh disease	II	III	nl		II
Removal of factor VIII inhibitors	II	II	III		III
Metabolic disorders
Hypercholesterolemia	II	I-II	I		I-II
Hypertriglyceridemia	nl	nl	nl		III
Pruritis associated with cholestasis	II	nl	nl		nl
Hepatic failure	III	III	nl		III
Graves' disease and thyroid storm	I	III	III		III
Insulin receptor antibodies	nl	nl	nl		nl
Dermatological disorders
Pemphigus vulgaris	III	II	nl		III
Bullous pemphigus	nl	II	nl		nl
Toxic epidermal necrolysis (Lyell syndrome)	nl	nl	nl		nl
Porphyria cutanea tarda	nl	nl	nl		nl
Psoriasis	III	IV	IV		nl
Rheumatological disorders
Systemic lupus erythematosus	II	II	nl		III-IV
Antiphospholipid syndrome/(lupus anticoagulant)	nl	nl	nl		III
Scleroderma	III	III	III		III
Rheumatoid arthritis/rheumatoid vasculitis	II	III	IV&II		II
Vasculitis	II	II	II		nl
Polymyositis/dermatomyositis	III	III/IV	IV		nl
Renal disease
Goodpasture syndrome	I	I	I		I
Rapidly progressive glomerulonephritis	I	II	II		III
Multiple myeloma, cast nephropathy	II	II	nl		III
Henoch-Schönlein purpura/IgA nephropathy	II	nl	nl		nl
Focal segmental glomerulosclerosis
Recurrence posttransplantation	nl	nl	nl		III
Renal allograft rejection	II	IV	IV		II
Removal of cytotoxic antibodies in the transplant candidate	nl	nl	nl		II
Indications for TPE in the ICU
Fulminant systemic meningococcemia	nl	nl	nl		nl
Endotoxemia	nl	nl	nl		III
Burn shock	III	nl	nl		nl
Human immunodeficiency virus	III	nl	nl		nl
Immune thrombocytopenic purpura	nl	II	nl		nl
Thrombotic thrombocytopenic purpura	nl	I	nl		nl
Peripheral neuropathy	nl	I	nl		nl
Intoxications	I	II	II		II-III
Arsine
Carbamazepine
Cisplatin
Digitoxin
Digoxin
Diltiazem
Mushroom poisoning		II			II
Paraquat		II
Parathion		II
Phenylbutazone
Phenytoin
Quinine
Sodium chlorate		II
Theophylline
Thyroxine
Tricyclic antidepressant
Vincristine

Note: Ratings: I, standard therapy, acceptable but not mandatory; II, available evidence tends to favor efficacy: conventional therapy usually tried first; III, inadequately tested at this time; IV, no demonstrated value in controlled trials; est, established therapy; invest, investigational; pos, possibly useful; nl, not listed.

Abbreviations: IgA, immunoglobulin A; TPE, therapeutic plasma exchange; ICU, intensive care unit.

Table 1 adapted with permission from Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan.

Another means of assessing the standard of care currently acceptable in the United States is to refer to the current indications for which Medicare is willing to reimburse. This list of indications is available on the Medicare website and is reproduced in Table 2.

Table 2.

Medicare Reimburseable Indications for Plasma Exchange⁎

	Apheresis is covered for the following indications:
	Plasma exchange for acquired myasthenia gravis
	Leukapheresis in the treatment of leukemia (cytapheresis)
	Plasmapheresis in the treatment of primary macroglobulinemia (Waldenstrom)
	Treatment of hyperglobulinemias, including (but not limited to) multiple myelomas, cryoglobulinemia, and hyperviscosity syndromes
	Plasmapheresis or plasma exchange as a last resort treatment of thromobotic thrombocytopenic purpura
	Plasmapheresis or plasma exchange in the last resort treatment of life-threatening rheumatoid vasculitis
	Plasma perfusion of charcoal filters for treatment of pruritis of cholestatic liver disease
	Plasma exchange in the treatment of Goodpasture syndrome
	Plasma exchange in the treatment of glomerulonephritis associated with anti–glomerular basement membrane antibodies and advancing renal failure or pulmonary hemorrhage
	Treatment of chronic relapsing polyneuropathy for patients with severe or life-threatening symptoms who have failed to respond to conventional therapy
	Treatment of life-threatening scleroderma and polymyositis when the patient is unresponsive to conventional therapy
	Treatment of Guillain-Barre syndrome
	Treatment of last resort for life-threatening systemic lupus erythematosus when conventional therapy has failed to prevent clinical deterioration

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

⁎

Centers for Medicare and Medicaid Services: NCD for Apheresis (therapeutic Pheresis). Available at: http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=110.14&ncd_version=1&basket=ncd%3A110%2E14%3A1%3AApheresis+%28Therapeutic+Pheresis%29. Accessed May 21, 2008.

Therapeutic Apheresis for Renal Disorders

Many primary renal diseases are associated with autoantibodies, rendering them appealing indications for TPE. Some indications are well established by randomized controlled studies and are considered standard of care (Goodpasture and thrombotic thrombocytopenic purpura [TTP]). Others have less compelling or only anecdotal supporting evidence.

I.Anti–Glomerular Basement Membrane (anti-GBM) Antibody–Mediated Disease (Goodpasture syndrome)A randomized controlled trial found TPE to provide a more rapid decrease in anti-GBM antibodies, lower posttreatment serum creatinine level, and decreased incidence of end-stage renal disease (ESRD). Given these results and the integral role of the anti-GBM antibody, TPE as a means of rapidly decreasing anti-GBM titers has become the standard of care.

A.Treatment strategy:

1.Early initiation of TPE is essential to avoid ESRD

2.Initial prescription is 14 daily 4-L exchanges

3.Continued apheresis may be required if antibody titers remain increased

4.Steroids, cyclophosphamide, or azathioprine are added to decrease production of anti-GBM antibody and minimize the inflammatory response

II.Crescentic Rapidly Progressive Glomerulonephritis (RPGN; not associated with anti-GBM antibody)Several controlled studies have failed to show a generalized benefit of TPE for all patients with RPGN; however, subset analysis of all these studies showed TPE to be beneficial for patients presenting with severe disease or dialysis dependency. A more recent study (Jayne et al) limited to patients presenting with creatinine levels greater than 5.8 mg/dL (to convert creatinine in mg/dL to μmol/L, multiply by 88.4) appears to support this conclusion (Table 3).

Table 3.

Controlled Trials of TPE for Patients With Severe or Dialysis-Dependent Rapidly Progressive Glomerulonephritis


Reference	Index of severity	TPE	no TPE
Mauri et al,1 1985	Creatinine > 9 mg/dL
Initial creatinine, mg/dL (no. of patients)		13.5(6)	13.1(5)
Creatinine after 3 y (mg/dL)		8.7⁎	13.4
Glockner et al,2 1988	Dialysis dependent
Initial creatinine, mg/dL (no. of patients)		7.4(8)	9.2(4)
Creatinine after 6 mo		1.7⁎	5.5
Pusey et al,3 1991	Dialysis dependent
Initial no. of patients on dialysis		11	8
Patients off dialysis at 12 mo		10†	3
Cole et al,4 1992	Dialysis dependent
Initial no. of patients on dialysis		4	7
Patients off dialysis at 12 mo		3	2
Jayne et al,5 2007	Creatinine > 5.8 mg/dL
Initial no. of patients		70	67
Patients off dialysis at 12 mo		57	40

Note: Subset analysis. All studies used concomitant treatment with steroids and immunosuppressive agents. To convert serum creatinine mg/dL to μmol/L, multiply by 88.4.

Abbreviation: TPE, therapeutic plasma exchange.

Table 3 adapted with permission from: Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan.

⁎

P < 0.05 with day 0.

†

P < 0.05, TPE versus no TPE.

Patients with Wegener granulomatosis and microscopic polyarteritis who present with pulmonary hemorrhage appear to be more likely to present with IgM antineutrophil cytoplasmic antibodies (ANCAs). These patients may also respond to TPE.

III.Renal Failure in Multiple MyelomaAfter exclusion of other forms of renal failure associated with multiple myeloma (eg, hypercalcemia, volume depletion, hyperuricemia, infection, and amyloidosis), patients considered to have light-chain–related “cast nephropathy” may benefit from TPE. TPE can decrease serum levels of light chains more rapidly than chemotherapy alone. A randomized controlled study found TPE to provide a more likely return of renal function and better overall survival (Zucchelli et al). However, despite a 50% decrease in need for dialysis, a recently reported study did not find a statistically significant benefit for TPE (Clark et al).

A.Treatment considerations:

1.Demonstration of free light chains in serum is essential if TPE is to be considered a rational treatment option (by standard immunofixation or the new free light chain assay)

2.Successful TPE prescription is 3 to 4 L of plasma exchanged on 5 consecutive days

3.Well-established (chronic) renal failure considered to be caused by cast nephropathy may respond less dramatically

4.Newly available highly permeable hemofilter membranes may allow for light chain removal without significant albumin loss (Hutchison et al)

IV.IgA Nephropathy and Henoch-Schönlein PurpuraCase reports and small clinical series suggest a possible beneficial effect of TPE in the treatment of IgA-associated RPGN.

V.CryoglobulinemiaDespite a lack of randomized controlled studies, most experts agree TPE can be a useful adjunct for severe active disease manifested by progressive renal failure, coalescing purpura, or advanced neuropathy. TPE can rapidly decrease cryoglobulin levels without the use of immunosuppressive agents, which might be problematic in hepatitis C–associated disease.

A.Treatment strategy:

1.A reasonable TPE prescription is to exchange 1 plasma volume 3 times weekly for 2 to 3 weeks

2.An average of 13 treatments may be required to induce clinical improvement (range, 4 to 39)

3.The replacement fluid can be 5% albumin, which must be warmed to prevent precipitation of circulating cryoglobulins

VI.TTP and Hemolytic Uremic Syndrome (HUS)

A.TTPA large randomized controlled study found 78% survival with TPE and fresh frozen plasma (FFP) replacement compared with 50% survival with FFP infusions alone (Rock et al). TPE with FFP replacement is the treatment of choice for TTP and is considered standard of care.

1.Treatment considerations:

i.FFP is required as replacement fluid to replace missing metalloprotease (ADAMTS13 [A Disintigrin-like And Metalloprotease with ThromboSpondin type 1 repeats])

ii.Plasma removal with TPE removes antibody to ADAMTS13

iii.Treatments are performed daily until the platelet count is normalized and hemolysis has largely ceased (normalization of lactate dehydrogenase)

iv.Exchanged volumes should be at least 1 plasma volume. Some experts recommend 1.5 plasma volume exchanges for the first week

v.Previous recommendations suggest switching to cryoprecipitate-poor plasma in resistant cases because it may contain lower levels of von Willebrand factor. However, a recent review suggests that cryoprecipitate-poor plasma contains less ADAMTS13 and may be less effective than FFP (Raife et al)

B.HUS in adultsAlthough renal failure tends to dominate the clinical presentation, unless a specific cause can be identified, HUS is often difficult to distinguish from TTP

1.Causes:

i.Verotoxin induced by Escherichia coli 0157-H7: prodrome of bloody diarrhea

ii.Drugs: cyclosporine, tacrolimus, mitomycin, cisplatinum, quinine, oral contraceptives, antiplatelet agents, and so on

iii.Lupus

iv.Cancer

v.Bone marrow transplant

vii.Posttransplantation recurrence

2.Prognosis in adults is poor:

i.Mortality between 25% and 50%

ii.ESRD in 40%

Although treatment success depends on the cause, HUS in adults is often treated with TPE as with TTP.

C.HUS in childrenPrognosis is usually good in verotoxin-induced disease, with only a small percentage of patients experiencing strokes or sustained renal failure. Controlled trials with plasma infusion have shown only minimal benefit.TPE may be beneficial in children:

1.Without a diarrheal prodrome

2.Older than 5 years

3.With significant central nervous system involvement

VII.Systemic Lupus ErythematosusRandomized controlled trials could not document systematic benefit of TPE when added to standard immunosuppressive therapy.TPE may still be useful in certain special situations:

A.Pregnancy, when cytotoxic agents are undesirable

B.Lupus-associated TTP

C.Lupus anticoagulant (LA)/antiphospholipid antibody syndrome

VIII.LA, Anticardiolipin Antibodies, and Antiphospholipid Antibody SyndromeLA and anticardiolipin antibody are antiphospholid antibodies associated with thromboses, recurrent fetal loss, and renal disease. TPE has been successful in removing antiphospholipid antibodies to avoid spontaneous abortion, treatment of LA-associated renal failure, and in the management of catastrophic antiphospholipid syndrome (CAPS).

IX.SclerodermaTPE may be useful in rare coexistence of scleroderma and ANCA-positive or antinuclear antibody (ANA)-positive renal disease.

X.Focal Segmental Glomerulosclerosis (FSGS): Recurrence PosttransplantationFifteen percent to 55% of patients with ESRD secondary to FSGS have rapid recurrence of proteinuria after renal transplantation. Some patients with early recurrence of proteinuria have a circulating 30- to 50,000-d protein capable of increasing glomerular permeability to albumin. Standard TPE and immunoadsorption have been successful in decreasing the level of proteinuria. The addition of cyclophosphamide to TPE may lead to more prolonged remission. TPE may be effective in the treatment of recurrent FSGS if treatment is initiated promptly after the initiation of proteinuria.

XII.Transplant Candidates With Cytotoxic AntibodiesTPE and immunoadsorption have been successful in decreasing high levels of preformed cytotoxic antibodies (panel reactive antibody [PRA]), allowing for successful transplants for up to 34 months.Often used with concomitant cyclophosphamide and prednisolone.

XIII.Renal Allograft RejectionTPE can provide a rapid decrease in anti-human leukocyte antigen (HLA) antibodies. However, 2 controlled trials of TPE for acute vascular rejection did not find this treatment to be useful.TPE together with cyclophosphamide and methylprednisolone has been reported to result in greater improvement in renal function and improved graft survival.

XIV.Renal Transplantation Across Blood Group Type ABO GroupsTPE can be used to remove anti-A or anti-B antibodies before transplantation. Five-year graft survival has been as high as 78% when kidneys from donors in blood A2 or B subgroups are transplanted into group O recipients. Donor-specific skin grafting can be used to predict outcome.

Plasmapheresis and Renal Disease: Suggested Readings

Reviews

Madore F, Lazarus JM, Brady HR: Therapeutic plasma exchange in renal disease. J Am Soc Nephrol 7:367-386, 1996

Kaplan AA: Therapeutic apheresis for renal disorders. Ther Apher 3:25-30, 1999

Anti-GBM Antibody–Mediated Disease

Johnson JP, Moore JJ, Austin H III, Balow JE, Antonovych TT, Wilson CB: Therapy of anti-glomerular basement membrane disease: Analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine 64:219-227, 1985

Savage CO, Pusey CD, Bowman C, Rees AJ, Lockwood CM: Antiglomerular basement membrane antibody-mediated disease in the British isles 1980-4. Br Med J 292:301-304, 1986

Rapidly Progressive Glomerulonephritis

Esnault VL, Soleimani B, Keogan MT, Brownlee AA, Jayne DR, Lockwood CM: Association of IgM with IgG ANCA in patients presenting with pulmonary hemorrhage. Kidney Int 41:1304-1310, 1992

Kaplan AA: Therapeutic plasma exchange for the treatment of rapidly progressive glomerulonephritis (RPGN). Ther Apher I:255-259, 1997

Jayne DR, Gaskin G, Rasmussen N, et al, for the European Vasculitis Study Group: Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 18:2180-2188, 2007

Lionaki S, Falk RJ: Removing antibody and preserving glomeruli in ANCA small-vessel vasculitis. J Am Soc Nephrol 18:1987-1989, 2007

Multiple Myeloma

Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 33:1175-1189, 1988

Clark WF, Stewart AK, Rock GA, et al: Plasma exchange when myeloma presents as acute renal failure: A randomized, controlled trial. Ann Intern Med 143:777-784, 2005

Rajkumar SV, Kaplan AA, Leung N: Treatment of renal failue in multiple myeloma, in Rose BD (ed): UpToDate. Waltham, MA, UpToDate, 2007

Hutchison CA, Cockwell P, Reid S, et al: Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: In vitro and in vivo studies. J Am Soc Nephrol 18:886-895, 2007

IgA Nephropathy and Henoch-Schönlein Purpura

Coppo R, Basolo B, Giachino O, et al: Plasmapheresis in a patient with rapidly progressive idiopathic IgA nephropathy: Removal of IgA-containing circulating immune complexes and clinical recovery. Nephron 40:488-490, 1985

Nicholls K, Becker G, Walker R, Wright C, Kincaid-Smith P: Plasma exchange in progressive IgA nephropathy. J Clin Apher 5:128-132, 1990

Cryoglobulinemia

Evans TW, Nicholls AJ, Shortland JR, Ward AM, Brown CB: Acute renal failure in essential mixed cryoglobulinemia: Precipitation and reversal by plasma exchange. Clin Nephrol 21:287-293, 1984

Ferri C, Moriconi L, Gremignai G, et al: Treatment of the renal involvement in mixed cryoglobulinemia with prolonged plasma exchange. Nephron 43:246-253, 1986

Thrombotic Thrombocytopenic Purpura

Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 325:393-397, 1991

Raife TJ, Friedman KD, Dwyre DM: The pathogenicity of vWF factor in TTP: Reconsideration of treatment with cryopoor plasma. Transfusion 46:74-79, 2006

HUS in the Adult

Melnyk AMS, Solez K, Kjellstrand CM: Adult hemolytic uremic syndrome: A review of 37 cases. Arch Intern Med 155:2077-2084, 1995

Agarwal A, Mauer SM, Matas AJ, Nath KA: Recurrent hemolytic uremic syndrome in an adult renal allograft recipient: Current concepts and management. J Am Soc Nephrol 6:1160-1169, 1995

Kaplan AA: Therapeutic apheresis for cancer related hemolytic uremic syndrome. Ther Apher 4:201-206, 2000

HUS in Children

Gianviti A, Perna A, Caringella A, et al: Plasma exchange in children with hemolytic-uremic syndrome at risk of poor outcome. Am J Kidney Dis 22:264-266, 1993

Sheth KJ, Leichter HE, Gill JC, Baumgardt A: Reversal of central nervous system involvement in hemolytic uremic syndrome by use of plasma exchange. Clin Pediatr 26:651-656, 1987

Systemic Lupus Erythematosus

Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM, for the Lupus Nephritis Collaborative Study Group: A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med 326:1373-1379, 1992

Antiphospholipid Antibody Syndrome

Asherson RA, Piette JC: The catastrophic antiphospholipid syndrome 1996: Acute multi-organ failure associated with antiphospholipid antibodies: A review of 31 patients. Lupus 5:414-417, 1996

Zar T, Kaplan AA: Predictable removal of anticardiolipin antibody by therapeutic plasma exchange in a patient with catastrophic antiphospholip antibody syndrome (CAPS). Clin Nephrol (in press)

Scleroderma

Endo H, Hosono T, Kondo H: Antineutrophil cytoplasmic autoantibodies in 6 patients with renal failure and systemic sclerosis. J Rheumatol 21:864-870, 1994

Wach F, Ullrich H, Schmitz G, Landthaler M, Hein R: Treatment of severe localized scleroderma by plasmapheresis—Report of three cases. Br J Dermatol 133:605-609, 1995

Focal Segmental Glomerulosclerosis

Dantal J, Bigot E, Bogers W, et al: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 330:7-14, 1994

Matalon A, Markowitz GS, Joseph RE, et al: Plasmapheresis treatment of recurrent FSGS in adult renal transplant recipients. Clin Nephrol 56:271-278, 2001

Cytotoxic Antibody Removal

Ross CN, Gaskin G, Gregor-Macgregor S, et al: Renal transplantation following immunoadsorption in highly sensitized recipients. Transplantation 55:785-789, 1993

Renal Allograft Rejection

Kirubakaran MG, Disney APS, Norman J, Pugsley DJ, Mathew TH: A controlled trial of plasmapheresis in the treatment of renal allograft rejection. Transplantation 32:164-165, 1981

Bonomini V, Vangelista A, Frasca GM, Di Felice A, Liviano D'Arcangelo G: Effects of plasmapheresis in renal transplant rejection: A controlled study. Trans Am Soc Artif Intern Organs 31:698-701, 1985

Renal Transplantation Across ABO Groups

Tanabe K, Takahashi K, Agishi T, et al: Removal of anti-A/B antibodies for successful kidney transplantation between ABO blood type incompatible couples. Transfus Sci 17:455-462, 1996

Karakayali H, Moray G, Demira A, et al: Long-term follow-up of ABO-incompatible renal transplant recipients. Transplant Proc 31:256-257, 1999

Takahashi K, Saito K, Takahara S, et al: Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 4:1089-1096, 2004

General Guidelines for Prescribing TPE

The amount of plasma to be exchanged during TPE must be determined in relation to the patient's estimated plasma volume (EPV). A simple means of estimating plasma volume can be calculated from the patient's weight and hematocrit using the following formula:

(1)

In general, large-molecular-weight substances (immunoglobulins, cholesterol-containing lipoproteins, and cryoglobulins) are only slowly equilibrated between their extravascular and intravascular distribution. Thus, removal during a single treatment essentially is limited to that in the intravascular compartment and the amount of plasma to be exchanged to provide a given decrease in pretreatment levels can be determined by application of first-order kinetics using the formula:

(2)

where X1 equals the final plasma concentration, Xo equals the initial concentration, and Ve equals the volume exchanged. (Of interest to nephrologists, the relation shown on this graph and the posttreatment percentage of reduction is exactly analogous to the Kt/V calculations associated with urea reduction ratios during dialysis in which Ve is Kt and EPV is V). The relation is plotted in Fig 1.

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Figure 1. Relation of volume exchanged, estimated plasma volume (EPV), and percentage of decrease in initial concentration for large-molecular-weight substances removed during therapeutic plasma exchange (TPE). For example, if the volume exchanged (Ve) is equal to the patient's EPV, Ve/EPV will equal 1 and pretreatment values will be decreased by 63%. If the plasma exchanged is equal to 1.4 times the EPV, pretreatment levels will be decreased by 75%. As shown in the figure, increasingly voluminous exchanges during a single treatment yield a progressively smaller decrease in pretreatment levels. For most indications, each treatment should provide an exchange volume equal to 1 to 1.4 times the EPV. (Reproduced from Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange, copyright Andre Kaplan)

Extravascular to intravascular reequilibration of a large-molecular-weight substance will be relatively slow (∼1% to 3% per hour). Thus, several consecutive treatments separated by 24 to 48 hours each will have to be performed to remove a substantial percentage of the total-body burden. An example of the progressive reduction in serum levels of an immunoglobulin is shown in Fig 2, with a net 70% decrease in total-body IgG level 1 day after 3 consecutive TPE treatments equaling 1 plasma volume each. In general, if production rates (resynthesis) are modest (ie, slowly forming antibody), at least 5 separate treatments during a 7- to 10-day period will be required to remove 90% of the patient's initial total-body burden. If production rates are high (ie, rapidly forming antibody, complement components), additional treatments may be required.

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Figure 2. Progressive decrease in immunoglobulin G (IgG) levels after 3 consecutive therapeutic plasma exchange (TPE) treatments equaling 1 plasma volume each. Intertreatment increases between treatments represent a combination of extravascular to intravascular reequilibration and a variable amount of new IgG synthesis. (Reproduced from Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange, copyright Andre Kaplan)

The results shown in Fig 2 describe a best-case scenario concerning immunoglobulin removal. In some autoimmune diseases, the rate of autoantibody production may greatly exceed that of the total immunoglobulin class. Such has been documented for certain cases of Goodpasture syndrome in which anti-GBM activity will be predictably decreased by a given plasma exchange treatment, but for which the intertreatment increases in serum levels are too rapid to be compatible with a simple reequilibration of extravascular stores. Thus, a 70% absolute decrease in a pathogenic autoantibody requires at least 3 plasma exchange treatments and may require a far more intensive treatment schedule if production rates cannot be adequately controlled by the concomitant immunosuppressive medications.

Production rates (half-lives), molecular weights, and percentages of intravascular distribution of several serum proteins are listed in Table 4.

Table 4.

Distribution and Metabolism of Plasma Proteins


Protein	Concentration (mg/mL)	MW × 103 d	Intravascular (%)	Fractional Turnover Rate (%/d)	Half-life (d)
Normal physiology
IgG (except IgG3 subclass)	12	150	45	7	22
IgG3	0.7	150	64	17	7
IgMa	0.9	950	78	19	5
IgA	2.5	160	42	25	6
IgD	0.02	175	75	37	2.8
IgE	0.0001	190	45	94	2.5
Albumin	45	66	44	11	17
C3	1.4	240	67	41	2
C4	0.5	200	66	43	2
Fibrinogen	3-4	340	81	24	4.2
Factor VIII	0.1	100-340	71	150	0.6
Antithrombin III	0.2	56-58	45	55	2.4
Lipoprotein cholesterol	1.5-2.0	1,300	>90		3-5
Pathological conditions
Macroglobulinemia, IgM	50-130	950	89	25⁎	5.9
Bence-Jones protein	4-10	10-25	<50	†	†
Endotoxin	3-25 × 10-7	100-2,400⁎	>50	‡	‡
Immune complexes	⁎	>300⁎	>50	‡	‡
Tumor necrosis factor	3-5 × 10-7	50 (trimer)	<50		6-20 min

Note: Values listed are averaged from those reported in the literature. Removal of a substance during a single TPE treatment will be limited to that which is intravascular. Substances with substantial extravascular distribution will require several consecutive TPE treatments to decrease total body burden. Substances with short half-lives (high turnover rate) will have a rapid return to pre-TPE levels unless production rates can be slowed by concomitant therapy.

Abbreviations: MW, molecular weight; TPE, therapeutic plasma exchange; IgG, immunoglobulin G.

Reproduced with permission from: Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan.

⁎

Highly variable or poorly defined.

†

Highly dependent on degree of renal function, half-life greatly increased with renal failure.

‡

Half life will be variable and dependent on the clearing capabilities of the reticuloendothelial system.

General Guidelines for TPE Prescription: Suggested Reading

Kaplan AA: A simple and accurate method for prescribing plasma exchange. Trans Am Soc Artif Intern Organs 36:M597-M599, 1990

Kaplan AA: Towards a rational prescription of plasma exchange: The kinetics of immunoglobulin removal. Semin Dial 5:227-229, 1992

Technique

Traditionally, plasma exchange was performed with centrifugation devices used in blood-banking procedures. These devices offer the advantage of allowing for selective cell removal (cytapheresis). Plasma exchange also can be performed using a highly permeable filter and standard dialysis equipment.

I.CentrifugationCentrifugation separates the plasma by density gradients.Whole-blood constituents are layered into plasma (specific gravity [SG], 1.025 to 1.109), platelets (SG, 1.040), lymph (SG, 1.070), granulocytes (SG, 1.087 to 1.092), and red blood cells (SG, 1.093 to 1.096).

II.Filtration (membrane plasma separation [MPS])Separation of plasma from the blood's cellular components can also be accomplished by filtration though a highly permeable membrane. Blood is separated into its cellular and noncellular components by subjecting it to sieving through a membrane with pores that allow plasma proteins to pass, but that retain the larger cellular elements within the blood path.

III.TPE With Dialysis EquipmentTPE can be performed with a highly permeable filter connected to the blood pump and pressure monitoring system of the dialysis machine. The machine is used in its “isolated” ultrafiltration mode, bypassing the dialysate proportioning system.

IV.AnticoagulationFor centrifugal techniques, anticoaglation is often provided by citrate. For MPS with dialysis equipment, heparin can be used as during standard dialysis.

VII.Replacement Fluids:

A.AlbuminPros: no viral transmission, allergies are rareCons: depletion coagulopathy, immunoglobulin depletion

1.Electrolyte compositionSodium, 145 ± 15 mEq/L; potassium, less than 2 mEq/L (sodium and potassium in mEq/L is equivalent to sodium and potassium in mmol/L)

2.Anaphylactic reactionsRare, antibodies to polymerized albumin?

3.“Depletion coagulopathy”Replacement with albumin will lead to depletion of coagulation factors.

i.After a single plasma exchange, prothrombin time (PT) increases 30%, partial thromboplastin time (PTT) doubles: these increases often reverse 1 day after treatment

ii.Multiple consecutive treatments result in prolonged increases in PT/PTT

iii.FFP administered toward the end of the procedure can minimize hemorrhagic risks

4.Immunoglobulin depletion

i.A single 1-plasma volume exchange reduces serum immunoglobulin levels by 60%

ii.Multiple treatments can decrease immunoglobulin levels for several weeks

iii.A single infusion of immunoglobulin (IVIG) administered after a series of TPE treatments can reconstitute normal immunoglobulin levels

5.Risk of viral transmissionAlbumin is heat treated and considered to be devoid of transmissible virus.

B.FFPPros: Does not lead to postpheresis coagulopathy or immunoglobulin depletion. FFP is essential for the treatment of TTP.Cons: Anaphylactoid reactions, citrate toxicity, small risk of viral transmission.

1.Anaphylactoid reactions

i.Fever, rigors, urticaria, wheezing, hypotension, and laryngeal edema

ii.Angiotensin-converting enzyme (ACE) inhibitors should be avoided given their ability to inhibit kinin metabolism

iii.Consider pretreatment with diphenhydramine intravenously (IV): 0.3 to 0.5 mL of epinephrine (1:1,000 solution) should be available for subcutaneous administration for severe reactions

2.Citrate toxicityFFP contains 14% citrate by volume; can lead to hypocalcemia and metabolic alkalosis

3.Risk of viral transmission1/63,000 units for hepatitis B, 1/100,000 units for hepatitis C, 1/680,000 units for human immunodeficiency virus (HIV), and 1/641,000 units for human T-lymphotrophic virus3 L of FFP is obtained from 10 to 15 donors (15 separate units).

C.Starch replacement for TPESimilar attributes with albumin, may be less expensive.

VIII.Vascular Access

A.Antecubital veins:

1.Ideal for low-flow treatments

2.Increasingly difficult to use after multiple punctures

B.Temporary vascular catheters:Catheter removal may be hazardous after an intensive run of TPE treatments, which can result in depletion coagulopathy and increased PT/PTT.

1.Femoral vein cannulation

2.Subclavian and internal jugular catheters

3.Tunneled jugular venous catheters

C.Permanent arteriovenous access:Preferred if treatments are to be repeated regularly (hyperlipidemia).

1.Primary arteriovenous fistula

2.Arteriovenous graft

IX.Selective Plasmapheresis Techniques

A.Designed to remove a particular pathogenic substance

B.Decreases need for replacement fluid

C.Minimizes risks of depletion coagulopathy and hypogammaglobulinemia

D.Many systems available in Japan and Europe, few in United States

1.Cascade filtration (“double filtration”)

i.Separated plasma is refiltered through a secondary filter with smaller pore size

ii.Larger, unwanted molecules removed by secondary filter

iii.Indications: Waldenstrom macroglobulinemia, cryoglobulinemia, familial hypercholesterolemia, and immune complex–mediated disease

2.Cryofiltration

i.Removed plasma is cooled, causing certain substances to aggregate

ii.Increasing size allows for efficient secondary filtration

iii.Indications: cyroglobulins and immune complexes

3.Immunoadsorbant techniques

i.Systems for selective immunoadsorption

ii.Indications: nonselective immunoglobulin removal, low- density lipoprotein (LDL) cholesterol.

a.Protein A columnsProtein A: 42,000-d protein released from Staphylococcus aureus. Used for the ex vivo adsorption of 3 of the 4 classes of IgG (1, 2, and 4).

aa.Prosorba column (Cypress Biosciences Inc, San Diego, CA)Single-use nonregenerating system placed in series with a standard plasma exchange circuit. When the plasma is separated from the blood, it is slowly perfused over the column (at 20 mL/min). This column saturates rapidly with very limited IgG removal. Postulated mode of action is by “immunomodulation” of perfused plasma.Food and Drug Administration approved for idiopathic thrombocytopenic purpura (ITP) and rheumatoid arthritis. Secondary effects are common: fever, chills, musculoskeletal pains, hypotension. Contraindicated in patients using ACE inhibitors.

bb.Excorim (Lund, Sweden)Alternating columns repeatedly regenerated to allow for more efficient IgG removalRenal indications: removal of anti-HLA antibodies in highly sensitized recipients, RPGN

4.Selective LDL cholesterol removal

i.Limits the loss of plasma proteins and high-density lipoprotein (HDL) cholesterol

ii.Indicated in patients with familial hypercholesterolemia who cannot tolerate or whose condition is unresponsive to pharmacological treatment and who have either known cardiovascular disease and a plasma LDL cholesterol level greater than 200 mg/dL or no known cardiovascular disease and a plasma LDL cholesterol level greater than 300 mg/dL

iii.Four systems:

a.Imunoadsorbant

b.Dextran sulfate binding to apoprotein BContraindication for patients on ACE-inhibitor therapy

c.Heparin-mediated extracorporal LDL precipitation (HELP)

d.Direct adsorption of LDL (DALI). Does not require plasma separation, removes LDL directly from whole blood

5.Endotoxin adsorption

i.Fibers impregnated with polymyxin B. Can bind endotoxin fragments

ii.Japanese experience documents improvement in systemic hemodynamics of sepsis

iii.Not currently available in the United States

Technique: Suggested Readings

Gurland HJ, Lysaght MJ, Samtleben W, Schmidt B: A comparison of centrifugal and membrane based apheresis formats. Int J Artif Organs 7:35-38, 1984

Centrifugation

Sowada K, Malchesky PS, Nose Y: Available removal systems: State of the art, in Nydegger UE (ed): Therapeutic Hemapheresis in the 1990s. Curr Stud Hematol Blood Transf 57:51-113, 1990

Membrane Plasma Separation

Gurland HJ, Lysaght MJ, Samtleben W, Schmidt B: Comparative evaluation of filters used in membrane plasmapheresis. Nephron 36:173-182, 1984

Sueoka A: Present status of apheresis technologies: Part 1. Membrane plasma separator. Ther Apher 1:42-48, 1997

TPE With Dialysis Equipment

Gerhardt RE, Ntoso KA, Koethe JD, Lodge S, Wolf CJ: Acute plasma separation with hemodialysis equipment. J Am Soc Nephrol 2:1455-1458, 1992

Price CA, McCarley PB: Technical considerations of therapeutic plasma exchange as a nephrology nursing procedure. ANNA J 20:41-46, 1993

Citrate Anticoagulation

Hester JP, McCullough J, Mishler JM, Szymanski IO: Dosage regimens for citrate anticoagulants. J Clin Apher 1:149-157, 1983

Replacement Fluids: Albumin

Finlayson JS: Albumin products. Semin Thromb Hemost 6:85-120, 1980

Replacement Fluids: FFP

AuBuchon JP, Birkmeyer JD, Busch MP: Safety of the blood supply in the United States: Opportunities and controversies. Ann Intern Med 127:904-909, 1997

Replacement Fluids: Starch

Brecher ME, Owen HG, Bandarenko N: Alternatives to albumin: Starch replacement for plasma exchange. J Clin Apher 12:146-153, 1997

Vascular Access

Mokrzycki MH, Zhang M, Golestaneh L, Laut J, Rosenberg SO: An interventional controlled trial comparing 2 management models for the treatment of tunneled cuffed catheter bacteremia: A collaborative team model versus usual physician-managed care. Am J Kidney Dis 48:587-595, 2006

Cascade Filtration Double Filtration

Agishi T, Kaneko I, Hasuo Y, et al: Double filtration plasmapheresis. Trans Am Soc Artif Intern Organs 26:406-409, 1980

Selective Plasmapheresis Techniques

Malchesky PS, Kaplan AA, Coo AP, Sadurada Y, Siami GA: Are selective macromolecule removal plasmapheresis systems useful for autoimmune diseases or hyperlipidemia? ASAIO J 39:868-872, 1993

Cryofiltration

Vibert GJ, Wirtz SA, Smith JW, et al: Cryofiltration as an alternative to plasma exchange: Plasma macromolecular solute removal without replacement fluids, in Nose Y, Malchesky PS, Smith JW (eds): Plasmapheresis. Cleveland, OH, ISAO, 1983, pp 281-287

Protein A Columns

Samtleben W, Schmidt B, Gurland HJ: Ex vivo and in vivo protein A perfusion: Background, basic investigations and first clinical experience. Blood Purif 5:179-192, 1987

Prosorba Column

Brecher ME, Owen Hg, Collins ML: Apheresis and ACE inhibitors. Transfusion 33:963-964, 1993 (letter)

Feldon DT, LeValley MP, Baldassare AR, et al. The Prosorba column for treatment of refractory rheumatoid arthritis. A randomized, double blind, sham controlled trial. Arthritis Rheum 42:2153-2159, 1999

Excorim

Hakim RM, Milford E, Himmelfarb J, Wingard R, Lazarus JM, Watt RM: Extracorporeal removal of anti-HLA antibodies in transplant candidates. Am J Kidney Dis 16:423-431, 1990

Ross CN, Gaskin G, Gregor-Macgregor S, et al: Renal transplantation following immunoadsorption in highly sensitized recipients. Transplantation 55:785-789, 1993

Selective Lipid Removal

Saal SD, Parker TS, Gordon BR: Removal of low-density lipoproteins in patients by extracorporeal immunoadsorption. Am J Med 80:583-589, 1986

Gordon BR, Kelsey SF, Bilheimer DW, et al: Treatment of refractory familial hypercholesterolemia by low density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Am J Cardiol 70:1010-1016, 1992

Busnach G, Cappelleri A, Vaccarino V, et al: Selective and semiselective low-density lipoprotein apheresis in familial hypercholesterolemia. Blood Purif 6:156-161, 1988

Kroon AA, van Asten WNJC, Stalenhoef AFH: Effect of apheresis of low-density lipoprotein on peripheral vascular disease in hypercholesterolemic patients with coronary artery disease. Ann Intern Med 125:945-954, 1996

Jovin IS, Taborski U, Stehr A, Müller-Berghaus G: Lipid reductions by low-density lipoprotein apheresis: A comparison of three systems. Metabolism 49:1431-1433, 2000

Bosch T, Gahr S, Belschner U, Schaefer C, Lennertz A, Rammo J, for the DALI Study Group: Direct adsorption of low-density lipoprotein by DALI-LDL-apheresis: Results of a prospective long-term multicenter follow-up covering 12,291 sessions. Ther Apher Dial 10: 210-218, 2006

Endotoxin Adsorption

Aoki H, Kodama M, Tani T, Hanasawa K: Treatment of sepsis by extracorporeal elimination of endotoxin using polymyxin B-immobilized fiber. Am J Surg 167:412-417, 1994

Complications

Most common: citrate-induced parethesias, muscle cramps, urticaria (Table 5).

Table 5.

Complications of Plasmapheresis


	Symptom	Percentage
	Urticaria	0.7-12
	Paresthesias	1.5-9
	Muscle cramps	0.4-2.5
	Dizziness	<2.5
	Headaches	0.3-5
	Nausea	0.1-1
	Hypotension	0.4-4.2
	Chest pain	0.03-1.3
	Arrhythmia	0.1-0.7
	Anaphylactoid reactions	0.03-0.7
	Rigors	1.1-8.8
	Hyperthermia	0.7-1.0
	Bronchospasm	0.1-0.4
	Seizure	0.03-0.4
	Respiratory arrest/pulmonary edema	0.2-0.3
	Myocardial ischemia	0.1
	Shock/myocardial infarction	0.1-1.5
	Metabolic alkalosis	0.03
	Disseminated intravascular coagulation	0.03
	Central nervous system ischemia	0.03-0.1
	Hepatitis	0.7
	Hemorrhage	0.2
	Hypoxemia	0.1
	Pulmonary embolism	0.1
	Access related
	Thrombosis/hemorrhage	0.02-0.7
	Infection	0.3
	Pneumothorax	0.1
	Mechanical	0.08-4

Adapted from Mokrzycki and Kaplan, Am J Kidney Dis 23:817, 1994. Reproduced from: Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan

Most serious: anaphylactoid reactions to FFP

Incidence of death is 0.05%, but many patients have severe preexisting conditions

I.Citrate-Induced Hypocalcemia

A.Citrate as anticoagulant or in FFP

B.Perioral or distal extremity tingling or paresthesias

C.Prophylactic replacement of IV calcium can reduce citrate-induced paresthesias

II.Coagulation Abnormalities

A.Depletion coagulopathy

1.After a single plasma exchange with albumin, clotting factors decrease by 60%

2.When multiple treatments are performed, depletion more pronounced

D.Thrombocytopenia

E.Anemia: hemorrhage associated with vascular access, treatment-related hemolysis

F.Thrombosis: hypercoaguable state from depletion of anticoagulant factors

III.Infection

A.Resulting from posttreatment depletion of immunoglobulinsManagement: IVIG (100 to 400 mg/kg IV)

B.Viral transmission from replacement fluid (FFP)

IV.Reactions to Protein Containing Replacement Fluids (FFP, purified protein fraction, albumin)Reactions to FFP are anaphylactoid in nature and characterized by fever, rigors, urticaria, wheezing, and hypotension and may eventually progress to laryngospasm.

V.Atypical Reactions Associated With ACE InhibitorsFlushing, hypotension, abdominal cramping, and severe anaplylactoid reactions have been reported with the dextran sulfate systems for selective lipid removal and in patients treated with the Prosorba column. Concurrent treatment with ACE inhibitors is considered contraindicated in patients treated with these selective removal techniques. ACE-inhibitor–induced inhibition of kinin metabolism may be unifying factor. Discontinuation of ACE inhibition should be accomplished well before initiation of these treatments. Timing of this discontinuation will depend on individual ACE-inhibitor half-life and pharmacodynamics.

VI.Electrolyte Abnormalities

A.Hypokalemia: albumin has potassium levels less than 2 mEq/L

B.Alkalosis: from citrate used for anticoagulation or in FFP

C.Aluminum: albumin solutions have 4 to 24 mmol/L of aluminumRisk of aluminum toxicity greatest with renal insufficiency

VII.Vitamin Removal

A.Vitamins B12, B6, A, C, and E and β-carotene decrease of 24% to 48%, but there is a rebound to pretreatment levels within 24 hours

B.Water-soluble vitamins, folate, thiamin, nicotinate, biotin, riboflavin, and pantothenate are not significantly altered by a single plasma exchange

C.Long-term effects of repetitive treatments are not known

VIII.Miscellaneous Complications

A.Apneic events in those anesthetized with succinylcholine due to low posttreatment levels of plasma cholinesterase

B.Hypotension, dyspnea, and chest pain secondary to complement-mediated membrane bioincompatibility

C.Anaphylactoid symptoms due to ethylene oxide sensitivity used as a sterilizing agent

D.Severe hemolysis as a result of hypotonic priming solutions or aggressive transmembrane pressure during MPS

E.Chills and hypothermia due to inadequately warmed replacement fluid

IX.Hypotension During TPE

A.Incidence of hypotension is 1.7%

B.Causes: see Table 6

Table 6.

Potential Causes for Hypotension During TPE

	Delayed or inadequate volume replacement
	Vasovagal episodes
	Hypo-oncotic fluid replacement: 3.5% albumin solutions
	Anaphylaxis:
	Reactions to plasma components in replacement fluids
	Anti-IgA antibodies (IgA-deficient patient)
	Endotoxin-contaminated replacement fluid
	Reactions to bioincompatible membranes
	Sensitivity to ethylene oxide
	Device-related: Prosorba protein A column
	Cardiac arrhythmia
	Citrate-induced hypocalcemia
	Hypokalemic related (especially in patients on digitalis therapy)
	Bradykinnin reactions (cf reactions to ACE inhibitors)
	Hemorrhage
	Associated with primary disease (ITP, factor VIII inhibitors)
	Associated with heparin anticoagulation
	Associated with vascular access
	External
	Internal
	“Depletion” coagulopathy
	Cardiovascular collapse
	Pulmonary embolus
	Disease-related hypotension
	Guillain-Barre syndrome (autonomic dysfunction)
	Waldenstrom macroglobulinemia (rapid decrease in plasma volume)

Abbreviations: IgA, immunoglobulin A; ACE, angiotensin-converting enzyme; ITP, idiopathic thrombocytopenic purpura; TPE, therapeutic plasma exchange.

Reproduced from: Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan.

X.Deaths

A.Incidence of 0.05%

B.Causes: cardiovascular, respiratory, and anaphylactic

i.Nonhemodynamic pulmonary edema (FFP replacement resulting in transfusion-related lung injury [TRALI])

ii.Cardiac arrhythmia

iii.Hemodynamic pulmonary edema

iv.Pulmonary embolism

XI.Drug RemovalWhen possible, all daily drug dosing should be administered after the TPE treatment.Drug removal is most dependent on percentage of protein binding and volume of distribution. Drugs with a high percentage of protein binding and a relatively modest volume of distribution (<0.3 L/kg) will have the greatest likelihood of being removed by TPE (Table 7). The replacement volume of a given TPE treatment would have to equal 0.7 times the volume of distribution of a drug to decrease pretreatment levels by 50%.

A.Specific drugs:

1.Not significantly removed by TPE:

i.Prednisone

ii.Prednisolone

2.Minimal removal:

i.Cyclophosphamide

ii.Azathioprine

iii.Aminoglycosides

iv.Tobramycin

v.Digoxin (removal of digibind-bound drug may be enhanced in patients with renal failure)

vi.Digitoxin

vii.Vancomycin

3.Posttreatment supplement may be necessary:

i.Phenytoin

ii.Acetylsalicylic acid

iii.Propranolol

iv.Thyroxine: 25% in the intravascular compartment 99% protein bound: TPE can treat thyroid storm

Table 7.

Drugs With a High Percentage of Protein Binding and Modest Volume of Distribution


	Protein Binding (%)	Volume of Distribution (L/kg)
Acetylsalicylic acid	50-90	0.1-0.2
Cefazolin	80	0.13-0.22
Cefotetan	85	0.15
Ceftriaxone	90	0.12-0.18
Chlorpropamide	72-96	0.09-0.27
Diclofenac	>99	0.12-0.17
Dicloxacillin	95	0.16
Glyburide	99	0.16-0.3
Heparin	>90	0.06-0.1
Ibuprofen	99	0.15-0.17
Indomethacin	99	0.12
Ketorolac	>99	0.13-0.25
Naproxen	99	0.10
Probenecid	85-95	0.15
Sodium valproate	90	0.19-0.23
Streptokinase	?	0.02-0.08
Tolbutamide	95-97	0.10-0.15
Warfarin	97-99	0.11-0.15

Note: In general, drugs with a high percentage of protein binding and a modest volume of distribution are likely to be removed by plasma exchange.

Reproduced from: Kaplan AA: A Practical Guide to Therapeutic Plasma Exchange. Blackwell Science, Malden, MA, 1999, copyright Andre Kaplan.

Complications: Suggested Readings

Sutton DMC, Nair RC, Rock G, and the Canadian Apheresis Study Group: Complications of plasma exchange. Transfusion 29:124-127, 1989

Mokrzycki MF, Kaplan AA: Therapeutic plasma exchange: Complications and management. Am J Kidney Dis 23:817-827, 1994

Citrate-Induced Hypocalcemia

Silberstein LE, Naryshkin S, Haddad JJ, Strauss JF: Calcium homeostasis during therapeutic plasma exchange. Transfusion 26:151-155, 1986

Coagulation Abnormalities

Wood L, Jacobs P: The effect of serial therapeutic plasmapheresis on platelet count, coagulation factors plasma immunoglobulin and complement levels. J Clin Apher 3:124-128, 1986

Sultan Y, Bussel A, Maisonneuve P, Sitty X, Gajdos P: Potential danger of thrombosis after plasma exchange in the treatment of patients with immune disease. Transfusion 19:588-593, 1979

Infection

Pohl MA, Lan SP, Berl T, and the Lupus Nephritis Collaborative Study Group: Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. Ann Intern Med 114:924-929, 1991

Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ: The risk of transfusion-transmitted virus invections. The Retrovirus Epidemiology Donor Study. N Engl J Med 334:1685-1690, 1996

Reactions to Protein-Containing Solutions

Apter AJ, Kaplan AA: An approach to immunologic reactions with plasma exchange. J Allergy Clin Immunol 90:119-124, 1992

Atypical Reactions to ACE Inhibitors

Owen HG, Brecher ME: Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion 34:891-894, 1994

Olbricht CJ, Schauman D, Fisher D: Anaphylactoid reactions, LDL apheresis with dextran sulfate and ACE inhibitors. Lancet 3:340:908-909, 1992

Electrolyte Abnormalities

Pearl RG, Rosenthal MH: Metabolic alkalosis due to plasmapheresis. Am J Med 79:391-393, 1985

Milliner DS, Shinaberger JH, Shurman P, Coburn JW: Inadvertent aluminum administration during plasma exchange due to aluminum contamination of albumin replacement solutions. N Engl J Med 312:165-167, 1985

Vitamin Removal

Reddi A, Frank O, DeAngelis B, et al: Vitamin status in patients undergoing single or multiple plasmapheresis. J Am Coll Nutr 6:485-489, 1987

Miscellaneous Complications

MacDonald R, Robinson A: Suxamethonium apnea associated with plasmapheresis. Anaesthesia 35:198-201, 1980

Jorstad S: Biocompatibility of different hemodialysis and plasmapheresis membranes. Blood Purif 5:123-137, 1987

Nicholls AJ, Platts MM: Anaphylactoid reactions due to haemodialysis, haemofiltration or membrane plasma separation. Br Med J 285:1607-1609, 1982

Deaths

Huestis DW: Mortality in therapeutic haemapheresis. Lancet 1:1043, 1983 (letter)

Drug Removal

Jones JV: The effect of plasmapheresis on therapeutic drugs. Dial Transplant 14:225-226, 1985

References for Table 1

1. 1American Medical Association Council on Scientific Affairs. Current status of therapeutic plasmapheresis. JAMA. 1985;253:819–825. MEDLINE

2. 2Strauss RG, Ciavarella D, Gilcher RO, et al. An overview of current management. J Clin Apher. 1993;8:189–194. MEDLINE | CrossRef

3. 3Leitman SF, Ciavarella D, McLeod B, Owen H, Price T, Sniecinski I. Guidelines for Therapeutic Hemapheresis. Bathesda, MD: American Association of Blood Banks; 1994;.

4. 4Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment of plasmapheresis (Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology). Neurology. 1996;47:840–843. MEDLINE

5. 5Szczepiorkowski ZM, Bandarenko N, Kim HC, et al. Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher. 2007;22:106–175. MEDLINE | CrossRef

References for Table 3

1. 1Mauri JM, Gonzales MT, Poveda R, et al. Therapeutic plasma exchange in the treatment of rapidly progressive glomerulonephritis. Plasma Ther Transfus Technol. 1985;6:587–591.

2. 2Glockner WM, Sieberth HG, Wichmann HE, et al. Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: A controlled multi-center study. Clin Nephrol. 1988;29:1–8.

3. 3Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CML. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int. 1991;40:757–763.

4. 4Cole E, Cattran D, Magil A, et al.Canadian Apheresis Study Group A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. Am J Kidney Dis. 1992;20:261–269.

5. 5Jayne DR, Gaskin G, Rasmussen N, et al.European Vasculitis Study Group Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18:2180–2188.

University of Connecticut Health Center, John Dempsey Hospital, and the UConn Dialysis Center, Farmington, CT

Address correspondence to Andre A. Kaplan, MD, University of Conneciticut Health Center, Division of Nephrology, MC 1405, Farmington, CT 06030

Originally published online as doi:10.1053/j.ajkd.2008.02.360 on June 17, 2008.

PII: S0272-6386(08)00707-5

doi:10.1053/j.ajkd.2008.02.360

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