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ORE CURRICULUM IN NEPHROLOGY
Therapeutic Plasma Exchange: Core Curriculum 2008
Andre A. Kaplan, MD
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iven their expertise in vascular access, antico-agulation, volume management, and solute
learance, nephrologists are well suited to managell methods of blood purification, including thera-eutic plasma exchange (TPE). This core curricu-um is an annotated primer and bibliography fornderstanding the indications, technique, and com-lications associated with TPE.
INTRODUCTION AND RATIONALE
TPE is an extracorporeal blood purification tech-ique designed for the removal of large-molecular-eight substances. Examples of these substances
nclude pathogenic autoantibodies, immune com-lexes, cryoglobulins, myeloma light chains, endo-oxin, and cholesterol-containing lipoproteins.
For TPE to be a rational choice as a bloodurification technique, at least 1 of the followingonditions should be met: (1) the substance to beemoved is sufficiently large (�15,000 d) toake other less expensive purification tech-
iques unacceptably inefficient (ie, hemofiltra-ion or high-flux dialysis), (2) the substance to beemoved has a comparatively prolonged half-lifeo that extracorporeal removal provides a thera-eutically useful period of diminished serumoncentration, and (3) the substance to be re-oved is acutely toxic and resistant to conven-
ional therapy so that the rapidity of extracorpo-eal removal is clinically indicated.
The removal of pathogenic autoantibodies of-ers an example. If one considers that the naturalalf-life of immunoglobulin G (IgG) is approxi-ately 21 days and assuming that an immunosup-
From the University of Connecticut Health Center, Johnempsey Hospital, and the UConn Dialysis Center, Farming-
on, CT.Received November 22, 2007. Accepted in revised formarch 10, 2008. Originally published online as doi:
0.1053/j.ajkd.2008.02.360 on June 17, 2008.Address correspondence to Andre A. Kaplan, MD, Univer-
ity of Conneciticut Health Center, Division of Nephrology,C 1405, Farmington, CT 06030. E-mail:
[email protected]© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5206-0021$34.00/0
Mdoi:10.1053/j.ajkd.2008.02.360
American Journal of Kidney180
ressive agent could immediately halt produc-ion (unlikely), serum levels would still be 50%f the initial values for at least 21 days afternitiating therapy. Such a delay might be unac-eptable in the presence of a very aggressiveutoantibody, such as that involved with Good-asture syndrome.
INTRODUCTION AND RATIONALE:SUGGESTED READINGS
Cohen S, Freeman T: Metabolic heterogeneity of human
amma globulin. Biochem J 76:475-487, 1960
INDICATIONS
In 1985, the American Medical AssociationAMA) Council on Scientific Affairs convened aanel of 10 experts to review the available dataor the efficacy of plasma exchange. Their assess-ent assigned each potential indication into 1 ofcategories:
I. Standard therapy, acceptable but not mandatoryII. Available evidence tends to favor efficacy:
conventional therapy usually tried firstII. Inadequately tested at this timeIV. No demonstrated value in controlled trials
Since this AMA review, there have been severalell-designed randomized controlled trials that
dded significant new insight into the proper appli-ation of TPE. In consideration of these new stud-es, 2 subsequent reviews have attempted to updatehe originalAMArecommendations.Added to thesepdated reviews is an assessment by the Americancademy of Neurology. Most recently, in June007, the American Society for Apheresis pub-ished their exhaustive review of the indications forlasma exchange and the most current assessmentf the available supportive evidence. The ratingystem of this most-up-to-date review uses catego-ies (I to IV) similar to the previous reviews.
The original AMA indications, updated andodified by the 4 subsequent reviews, are listed
n Table 1.Another means of assessing the standard of
are currently acceptable in the United States iso refer to the current indications for which
edicare is willing to reimburse. This list of
Diseases, Vol 52, No 6 (December), 2008: pp 1180-1196
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Core Curriculum in Nephrology 1181
Table 1. Indications for TPE
Reference 1 2 3 4 5
Year 1986 1993 1994 1996 2007
Rating Rating Rating Rating Rating
eurological diseasesGuillain-Barre syndrome I I I est IMyasthenia gravis I I I est IChronic inflammatory demyelinating polyneuropathy III I I est IParaprotein-associated polyneuropathy nl II nl est I-IIIMultiple sclerosis II III III pos II-IIIEaton Lambert syndrome nl I nl pos IIStiff man syndrome nl nl nl invest IIIAmyotrophic lateral sclerosis IV IV IV nl nlNeuromyotonia nl nl nl invest nlAcute disseminated encephalomyelitis nl nl nl invest IIIRefsum’s disease nl I nl invest IISensorineural hearing loss nl nl nl nl nl
ematologic disordersHyperviscosity syndrome I I I ICryoglobulinemia II I I IThrombotic thrombocytopenic purpura I I I IHemolytic uremic syndrome nl II II III-IVIdiopathic thrombocytopenic purpura III III III II-IVPosttransfusion purpura II I I IIIAutoimmune hemolytic anemia III III III IIIMaternal-fetal incompatibility-Rh disease II III nl IIRemoval of factor VIII inhibitors II II III IIIetabolic disordersHypercholesterolemia II I-II I I-IIHypertriglyceridemia nl nl nl IIIPruritis associated with cholestasis II nl nl nlHepatic failure III III nl IIIGraves’ disease and thyroid storm I III III IIIInsulin receptor antibodies nl nl nl nl
ermatological disordersPemphigus vulgaris III II nl IIIBullous pemphigus nl II nl nlToxic epidermal necrolysis (Lyell syndrome) nl nl nl nlPorphyria cutanea tarda nl nl nl nlPsoriasis III IV IV nl
heumatological disordersSystemic lupus erythematosus II II nl III-IVAntiphospholipid syndrome/(lupus anticoagulant) nl nl nl IIIScleroderma III III III IIIRheumatoid arthritis/rheumatoid vasculitis II III IV&II IIVasculitis II II II nlPolymyositis/dermatomyositis III III/IV IV nl
enal diseaseGoodpasture syndrome I I I IRapidly progressive glomerulonephritis I II II IIIMultiple myeloma, cast nephropathy II II nl IIIHenoch-Schönlein purpura/IgA nephropathy II nl nl nlFocal segmental glomerulosclerosis
Recurrence posttransplantation nl nl nl IIIRenal allograft rejection II IV IV IIRemoval of cytotoxic antibodies in the transplant candidate nl nl nl II
(Continued)
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Andre A. Kaplan1182
ndications is available on the Medicare websitend is reproduced in Table 2.
herapeutic Apheresis for Renal Disorders
Many primary renal diseases are associated
Table 1 (Cont’d)
Reference
Year
ndications for TPE in the ICUFulminant systemic meningococcemiaEndotoxemiaBurn shockHuman immunodeficiency virusImmune thrombocytopenic purpuraThrombotic thrombocytopenic purpuraPeripheral neuropathy
ntoxicationsArsineCarbamazepineCisplatinDigitoxinDigoxinDiltiazemMushroom poisoningParaquatParathionPhenylbutazonePhenytoinQuinineSodium chlorateTheophyllineThyroxineTricyclic antidepressantVincristine
Note: Ratings: I, standard therapy, acceptable but nonventional therapy usually tried first; III, inadequately tesstablished therapy; invest, investigational; pos, possibly uAbbreviations: IgA, immunoglobulin A; TPE, therapeuticTable 1 adapted with permission from Kaplan AA: A Pracalden, MA, 1999, copyright Andre Kaplan.
REFERENCE1. American Medical Association Council on Scientifi
53:819-825, 19852. Strauss RG, Ciavarella D, Gilcher RO, et al: An overvi3. Leitman SF, Ciavarella D, McLeod B, Owen H, Price TD, American Association of Blood Banks, 19944. Therapeutics and Technology Assessment Subcomm
lasmapheresis. Neurology 47:840-843, 19965. Szczepiorkowski ZM, Bandarenko N, Kim HC, et al:
vidence-based approach from the Apheresis Applications2:106-175, 2007
ith autoantibodies, rendering them appealing a
ndications for TPE. Some indications are wellstablished by randomized controlled studies andre considered standard of care (Goodpasturend thrombotic thrombocytopenic purpuraTTP]). Others have less compelling or only
ations for TPE
1 2 3 5
1986 1993 1994 2007
Rating Rating Rating Rating
nl nl nl nlnl nl nl IIIIII nl nl nlIII nl nl nlnl II nl nlnl I nl nlnl I nl nlI II II II-III
II IIIIII
II
ndatory; II, available evidence tends to favor efficacy:his time; IV, no demonstrated value in controlled trials; est,l, not listed.exchange; ICU, intensive care unit.
uide to Therapeutic Plasma Exchange. Blackwell Science,
R TABLE 1rs: Current status of therapeutic plasmapheresis. JAMA
urrent management. J Clin Apher 8:189-194, 1993inski I: Guidelines for Therapeutic Hemapheresis. Bathesda,
f the American Academy of Neurology: Assessment of
nes on the use of therapeutic apheresis in clinical practice:ittee of the American Society for Apheresis. J Clin Apher
. Indic
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Core Curriculum in Nephrology 1183
I. Anti–Glomerular Basement Membrane(anti-GBM) Antibody–Mediated Disease(Goodpasture syndrome)
A randomized controlled trial foundTPE to provide a more rapid decrease inanti-GBM antibodies, lower posttreat-ment serum creatinine level, and de-creased incidence of end-stage renal dis-ease (ESRD). Given these results and theintegral role of the anti-GBM antibody,TPE as a means of rapidly decreasinganti-GBM titers has become the standardof care.A. Treatment strategy:
1. Early initiation of TPE is essentialto avoid ESRD
2. Initial prescription is 14 daily 4-Lexchanges
3. Continued apheresis may be re-quired if antibody titers remain in-creased
4. Steroids, cyclophosphamide, orazathioprine are added to decreaseproduction of anti-GBM antibodyand minimize the inflammatoryresponse
II. Crescentic Rapidly Progressive Glomeru-lonephritis (RPGN; not associated with
Table 2. Medicare Reimburseab
pheresis is covered for the following indications:Plasma exchange for acquired myasthenia gravisLeukapheresis in the treatment of leukemia (cytapheresiPlasmapheresis in the treatment of primary macroglobulTreatment of hyperglobulinemias, including (but not limitsyndromesPlasmapheresis or plasma exchange as a last resort treaPlasmapheresis or plasma exchange in the last resort trePlasma perfusion of charcoal filters for treatment of pruriPlasma exchange in the treatment of Goodpasture syndrPlasma exchange in the treatment of glomerulonephritisantibodies and advancing renal failure or pulmonary hemTreatment of chronic relapsing polyneuropathy for patienrespond to conventional therapyTreatment of life-threatening scleroderma and polymyosTreatment of Guillain-Barre syndromeTreatment of last resort for life-threatening systemic lupuprevent clinical deterioration
Note: This may not be an exhaustive list of all applicable*Centers for Medicare and Medicaid Services: NCDww.cms.hhs.gov/mcd/viewncd.asp?ncd_id�110.14&nAApheresis�%28Therapeutic�Pheresis%29. Accessed
anti-GBM antibody)
Several controlled studies have failed toshow a generalized benefit of TPE for allpatients with RPGN; however, subset anal-ysis of all these studies showed TPE to bebeneficial for patients presenting with se-vere disease or dialysis dependency. Amore recent study (Jayne et al) limited topatients presenting with creatinine levelsgreater than 5.8 mg/dL (to convert creati-nine in mg/dL to �mol/L, multiply by88.4) appears to support this conclusion(Table 3).
Patients with Wegener granulomatosisand microscopic polyarteritis who presentwith pulmonary hemorrhage appear to bemore likely to present with IgM antineutro-phil 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, hy-peruricemia, infection, and amyloidosis),patients considered to have light-chain–related “cast nephropathy” may benefitfrom TPE. TPE can decrease serum levelsof light chains more rapidly than chemo-therapy alone. A randomized controlled
ications for Plasma Exchange*
(Waldenstrom)ultiple myelomas, cryoglobulinemia, and hyperviscosity
of thromobotic thrombocytopenic purpurat of life-threatening rheumatoid vasculitisolestatic liver disease
ated with anti–glomerular basement membraneesevere or life-threatening symptoms who have failed to
n the patient is unresponsive to conventional therapy
ematosus when conventional therapy has failed to
re benefit categories for this item or service.Apheresis (therapeutic Pheresis). Available at: http://sion�1&basket�ncd%3A110%2E14%3A1%, 2008.
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Andre A. Kaplan1184
return of renal function and better overallsurvival (Zucchelli et al). However, de-spite a 50% decrease in need for dialysis, arecently reported study did not find astatistically significant benefit for TPE(Clark et al).A. Treatment considerations:
1. Demonstration of free light chainsin serum is essential if TPE is to beconsidered a rational treatment op-tion (by standard immunofixation orthe new free light chain assay)
2. Successful TPE prescription is 3 to4 L of plasma exchanged on 5consecutive days
3. Well-established (chronic) renal fail-
Table 3. Controlled Trials of TPE for Patients WGlomer
Reference
auri et al,1 1985 CreInitial creatinine, mg/dL (no. of patients)Creatinine after 3 y (mg/dL)lockner et al,2 1988 DiaInitial creatinine, mg/dL (no. of patients)Creatinine after 6 mo
usey et al,3 1991 DiaInitial no. of patients on dialysisPatients off dialysis at 12 mo
ole et al,4 1992 DiaInitial no. of patients on dialysisPatients off dialysis at 12 mo
ayne et al,5 2007 CreInitial no. of patientsPatients off dialysis at 12 mo
Note: Subset analysis. All studies used concomitant treaerum creatinine mg/dL to �mol/L, multiply by 88.4.Abbreviation: TPE, therapeutic plasma exchange.Table 3 adapted with permission from: Kaplan AA: A Pracalden, MA, 1999, copyright Andre Kaplan.*P � 0.05 with day 0.†P � 0.05, TPE versus no TPE.
REFERENC1. Mauri JM, Gonzales MT, Poveda R, et al: Therap
lomerulonephritis. Plasma Ther Transfus Technol 6:587-5912. Glockner WM, Sieberth HG, Wichmann HE, et al: P
lomerulonephritis: A controlled multi-center study. Clin Ne3. Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood
ithout anti-GBM antibodies. Kidney Int 40:757-763, 19914. Cole E, Cattran D, Magil A, et al, for the Canadian A
xchange as additive therapy in idiopathic crescentic glomer5. Jayne DR, Gaskin G, Rasmussen N, et al, for the Europ
r high-dosage methylprednisolone as adjunctive therapy for
ure considered to be caused by cast
nephropathy may respond less dra-matically
4. Newly available highly permeablehemofilter membranes may allow forlight chain removal without signifi-cant albumin loss (Hutchison et al)
IV. IgA Nephropathy and Henoch-SchönleinPurpura
Case reports and small clinical seriessuggest a possible beneficial effect of TPEin the treatment of IgA-associated RPGN.
V. CryoglobulinemiaDespite a lack of randomized controlled
studies, most experts agree TPE can be auseful adjunct for severe active diseasemanifested by progressive renal failure,
ere or Dialysis-Dependent Rapidly Progressivephritis
of severity TPE no TPE
� 9 mg/dL13.5 (6) 13.1 (5)
8.7* 13.4ependent
7.4 (8) 9.2 (4)1.7* 5.5
ependent11 810† 3
ependent4 73 2
� 5.8 mg/dL70 6757 40
with steroids and immunosuppressive agents. To convert
uide to Therapeutic Plasma Exchange. Blackwell Science,
R TABLE 3lasma exchange in the treatment of rapidly progressive
exchange and immunosuppression in rapidly progressive9:1-8, 1988: Plasma exchange in focal necrotizing glomerulonephritis
is Study Group: A prospective randomized trial of plasmaritis. Am J Kidney Dis 20:261-269, 1992sculitis Study Group: Randomized trial of plasma exchangerenal vasculitis. J Am Soc Nephrol 18:2180-2188, 2007
ith Sevulone
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Core Curriculum in Nephrology 1185
athy. TPE can rapidly decrease cryo-globulin levels without the use of immu-nosuppressive agents, which might beproblematic in hepatitis C–associateddisease.A. Treatment strategy:
1. A reasonable TPE prescription is toexchange 1 plasma volume 3 timesweekly for 2 to 3 weeks
2. An average of 13 treatments may berequired to induce clinical improve-ment (range, 4 to 39)
3. The replacement fluid can be 5%albumin, which must be warmed toprevent precipitation of circulatingcryoglobulins
VI. TTP and Hemolytic Uremic Syndrome(HUS)A. TTP
A large randomized controlled studyfound 78% survival with TPE and freshfrozen plasma (FFP) replacement com-pared with 50% survival with FFPinfusions alone (Rock et al). TPE withFFP replacement is the treatment ofchoice for TTP and is considered stan-dard of care.1. Treatment considerations:
i. FFP is required as replacementfluid to replace missing metallo-protease (ADAMTS13 [ADisin-tigrin-like And Metalloproteasewith ThromboSpondin type 1repeats])
ii. Plasma removal with TPE re-moves antibody to ADAMTS13
iii. Treatments are performed dailyuntil the platelet count is normal-ized and hemolysis has largelyceased (normalization of lactatedehydrogenase)
iv. Exchanged volumes should beat least 1 plasma volume. Someexperts recommend 1.5 plasmavolume exchanges for the firstweek
v. Previous recommendations sug-gest switching to cryoprecipi-tate-poor plasma in resistantcases because it may contain
lower levels of von Willebrandfactor. However, a recent re-view suggests that cryoprecipi-tate-poor plasma contains lessADAMTS13 and may be lesseffective than FFP (Raife et al)
B. HUS in adultsAlthough renal failure tends to domi-
nate the clinical presentation, unless aspecific cause can be identified, HUS isoften difficult to distinguish from TTP1. Causes:
i. Verotoxin induced by Esche-richia coli 0157-H7: prodromeof bloody diarrhea
ii. Drugs: cyclosporine, tacroli-mus, mitomycin, cisplatinum,quinine, oral contraceptives, an-tiplatelet agents, and so on
iii. Lupusiv. Cancerv. Bone marrow transplant
vii. Posttransplantation recurrence2. Prognosis in adults is poor:
i. Mortality between 25% and 50%ii. ESRD in 40%
Although treatment success dependson the cause, HUS in adults is oftentreated with TPE as with TTP.
C. HUS in childrenPrognosis is usually good in vero-
toxin-induced disease, with only a smallpercentage of patients experiencingstrokes or sustained renal failure. Con-trolled trials with plasma infusion haveshown only minimal benefit.
TPE may be beneficial in children:1. Without a diarrheal prodrome2. Older than 5 years3. With significant central nervous sys-
tem involvementVII. Systemic Lupus Erythematosus
Randomized controlled trials could notdocument systematic benefit of TPE whenadded to standard immunosuppressivetherapy.
TPE may still be useful in certainspecial situations:A. Pregnancy, when cytotoxic agents are
undesirable
B. Lupus-associated TTP
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Andre A. Kaplan1186
C. Lupus anticoagulant (LA)/antiphospho-lipid antibody syndrome
III. LA, Anticardiolipin Antibodies, and An-tiphospholipid Antibody Syndrome
LA and anticardiolipin antibody areantiphospholid antibodies associated withthromboses, recurrent fetal loss, and renaldisease. TPE has been successful in remov-ing antiphospholipid antibodies to avoidspontaneous abortion, treatment of LA-associated renal failure, and in the manage-ment of catastrophic antiphospholipid syn-drome (CAPS).
IX. SclerodermaTPE may be useful in rare coexistence
of scleroderma and ANCA-positive or an-tinuclear antibody (ANA)-positive renaldisease.
X. Focal Segmental Glomerulosclerosis(FSGS): Recurrence Posttransplantation
Fifteen percent to 55% of patients withESRD secondary to FSGS have rapid recur-rence of proteinuria after renal transplanta-tion. Some patients with early recurrence ofproteinuria have a circulating 30- to 50,000-dprotein capable of increasing glomerularpermeability to albumin. Standard TPE andimmunoadsorption have been successful indecreasing the level of proteinuria. The addi-tion of cyclophosphamide to TPE may leadto more prolonged remission. TPE may beeffective in the treatment of recurrent FSGSif treatment is initiated promptly after theinitiation of proteinuria.
XII. Transplant Candidates With Cytotoxic An-tibodies
TPE and immunoadsorption have beensuccessful in decreasing high levels ofpreformed cytotoxic antibodies (panel re-active antibody [PRA]), allowing for suc-cessful transplants for up to 34 months.
Often used with concomitant cyclophos-phamide and prednisolone.
III. Renal Allograft RejectionTPE can provide a rapid decrease in
anti-human leukocyte antigen (HLA) anti-bodies. However, 2 controlled trials ofTPE for acute vascular rejection did notfind this treatment to be useful.
TPE together with cyclophosphamide
and methylprednisolone has been reported mto result in greater improvement in renalfunction and improved graft survival.
XIV. Renal Transplantation Across Blood GroupType ABO Groups
TPE can be used to remove anti-A oranti-B antibodies before transplantation.Five-year graft survival has been as highas 78% when kidneys from donors inblood A2 or B subgroups are transplantedinto group O recipients. Donor-specificskin grafting can be used to predictoutcome.
PLASMAPHERESIS AND RENAL DISEASE:SUGGESTED READINGS
eviews:
Madore F, Lazarus JM, Brady HR: Therapeutic plasmaxchange in renal disease. J Am Soc Nephrol 7:367-386,996
Kaplan AA: Therapeutic apheresis for renal disorders.her Apher 3:25-30, 1999
nti-GBM Antibody–Mediated Disease:
Johnson JP, Moore JJ, Austin H III, Balow JE, An-onovych TT, Wilson CB: Therapy of anti-glomerular base-ent membrane disease: Analysis of prognostic significance
f clinical, pathologic and treatment factors. Medicine 64:19-227, 1985
Savage CO, Pusey CD, Bowman C, Rees AJ, LockwoodM: Antiglomerular basement membrane antibody-medi-ted disease in the British isles 1980-4. Br Med J 292:301-04, 1986
apidly Progressive Glomerulonephritis:
Esnault VL, Soleimani B, Keogan MT, Brownlee AA,ayne DR, Lockwood CM: Association of IgM with IgGNCA in patients presenting with pulmonary hemorrhage.idney Int 41:1304-1310, 1992Kaplan AA: Therapeutic plasma exchange for the treat-
ent of rapidly progressive glomerulonephritis (RPGN).her Apher I:255-259, 1997
Jayne DR, Gaskin G, Rasmussen N, et al, for the Euro-ean Vasculitis Study Group: Randomized trial of plasmaxchange or high-dosage methylprednisolone as adjunctiveherapy for severe renal vasculitis. J Am Soc Nephrol8:2180-2188, 2007
Lionaki S, Falk RJ: Removing antibody and preservinglomeruli in ANCA small-vessel vasculitis. J Am Soc Neph-ol 18:1987-1989, 2007
ultiple Myeloma:
Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlledlasma exchange trial in acute renal failure due to multiple
yeloma. Kidney Int 33:1175-1189, 1988
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Core Curriculum in Nephrology 1187
Clark WF, Stewart AK, Rock GA, et al: Plasma exchangehen myeloma presents as acute renal failure: A random-
zed, controlled trial. Ann Intern Med 143:777-784, 2005Rajkumar SV, Kaplan AA, Leung N: Treatment of renal
ailue in multiple myeloma, in Rose BD (ed): UpToDate.altham, MA, UpToDate, 2007Hutchison CA, Cockwell P, Reid S, et al: Efficient
emoval of immunoglobulin free light chains by hemodialy-is for multiple myeloma: In vitro and in vivo studies. J Amoc Nephrol 18:886-895, 2007
gA Nephropathy and Henoch-Schönleinurpura:
Coppo R, Basolo B, Giachino O, et al: Plasmapheresis inpatient with rapidly progressive idiopathic IgA nephropa-
hy: Removal of IgA-containing circulating immune com-lexes and clinical recovery. Nephron 40:488-490, 1985
Nicholls K, Becker G, Walker R, Wright C, Kincaid-mith P: Plasma exchange in progressive IgA nephropathy.Clin Apher 5:128-132, 1990
ryoglobulinemia:
Evans TW, Nicholls AJ, Shortland JR, Ward AM, BrownB: Acute renal failure in essential mixed cryoglobuline-ia: Precipitation and reversal by plasma exchange. Clinephrol 21:287-293, 1984Ferri C, Moriconi L, Gremignai G, et al: Treatment of the
enal involvement in mixed cryoglobulinemia with pro-onged plasma exchange. Nephron 43:246-253, 1986
hrombotic Thrombocytopenic Purpura:
Rock GA, Shumak KH, Buskard NA, et al: Comparisonf plasma exchange with plasma infusion in the treatment ofhrombotic thrombocytopenic purpura. N Engl J Med 325:93-397, 1991
Raife TJ, Friedman KD, Dwyre DM: The pathogenicityf vWF factor in TTP: Reconsideration of treatment withryopoor plasma. Transfusion 46:74-79, 2006
US in the Adult:
Melnyk AMS, Solez K, Kjellstrand CM: Adult hemolyticremic syndrome: A review of 37 cases. Arch Intern Med55:2077-2084, 1995
Agarwal A, Mauer SM, Matas AJ, Nath KA: Recurrentemolytic uremic syndrome in an adult renal allograft recipi-nt: Current concepts and management. J Am Soc Nephrol:1160-1169, 1995
Kaplan AA: Therapeutic apheresis for cancer relatedemolytic uremic syndrome. Ther Apher 4:201-206, 2000
US in Children:
Gianviti A, Perna A, Caringella A, et al: Plasma exchangen children with hemolytic-uremic syndrome at risk of poorutcome. Am J Kidney Dis 22:264-266, 1993
Sheth KJ, Leichter HE, Gill JC, Baumgardt A: Reversal
f central nervous system involvement in hemolytic uremic ayndrome by use of plasma exchange. Clin Pediatr 26:651-56, 1987
ystemic Lupus Erythematosus:
Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM,or the Lupus Nephritis Collaborative Study Group: A con-rolled trial of plasmapheresis therapy in severe lupus nephri-is. N Engl J Med 326:1373-1379, 1992
ntiphospholipid Antibody Syndrome:
Asherson RA, Piette JC: The catastrophic antiphospho-ipid syndrome 1996: Acute multi-organ failure associatedith antiphospholipid antibodies: A review of 31 patients.upus 5:414-417, 1996
Zar T, Kaplan AA: Predictable removal of anticardiolipinntibody by therapeutic plasma exchange in a patient withatastrophic antiphospholip antibody syndrome (CAPS). Clinephrol (in press)
cleroderma:
Endo H, Hosono T, Kondo H: Antineutrophil cytoplasmicutoantibodies in 6 patients with renal failure and systemicclerosis. J Rheumatol 21:864-870, 1994
Wach F, Ullrich H, Schmitz G, Landthaler M, Hein R:reatment of severe localized scleroderma by plasmaphere-is—Report of three cases. Br J Dermatol 133:605-609,995
ocal Segmental Glomerulosclerosis:
Dantal J, Bigot E, Bogers W, et al: Effect of plasmarotein adsorption on protein excretion in kidney-transplantecipients with recurrent nephrotic syndrome. N Engl J Med30:7-14, 1994
MatalonA, Markowitz GS, Joseph RE, et al: Plasmaphere-is treatment of recurrent FSGS in adult renal transplantecipients. Clin Nephrol 56:271-278, 2001
ytotoxic Antibody Removal:
Ross CN, Gaskin G, Gregor-Macgregor S, et al: Renalransplantation following immunoadsorption in highly sensi-ized recipients. Transplantation 55:785-789, 1993
enal Allograft Rejection:
Kirubakaran MG, Disney APS, Norman J, Pugsley DJ,athew TH: A controlled trial of plasmapheresis in the
reatment of renal allograft rejection. Transplantation 32:164-65, 1981
Bonomini V, Vangelista A, Frasca GM, Di Felice A,iviano D’Arcangelo G: Effects of plasmapheresis in renal
ransplant rejection: A controlled study. Trans Am Soc Artifntern Organs 31:698-701, 1985
enal Transplantation Across ABO Groups:
Tanabe K, Takahashi K, Agishi T, et al: Removal of
nti-A/B antibodies for successful kidney transplantation
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Andre A. Kaplan1188
etween ABO blood type incompatible couples. Transfusci 17:455-462, 1996
Karakayali H, Moray G, Demira A, et al: Long-termollow-up of ABO-incompatible renal transplant recipients.ransplant Proc 31:256-257, 1999
Takahashi K, Saito K, Takahara S, et al: Excellent long-erm outcome of ABO-incompatible living donor kidneyransplantation in Japan. Am J Transplant 4:1089-1096,004
GENERAL GUIDELINES FOR PRESCRIBING TPE
The amount of plasma to be exchanged duringPE must be determined in relation to the pa-
ient’s estimated plasma volume (EPV). A simpleeans of estimating plasma volume can be calcu-
ated from the patient’s weight and hematocritsing the following formula:
PV � (0.065 � weight �kg�)� (1 � hematocrit) (1)
n general, large-molecular-weight substancesimmunoglobulins, cholesterol-containing li-oproteins, and cryoglobulins) are only slowlyquilibrated between their extravascular and in-ravascular distribution. Thus, removal during aingle treatment essentially is limited to that inhe intravascular compartment and the amount oflasma to be exchanged to provide a given de-rease in pretreatment levels can be determinedy application of first-order kinetics using theormula:
X1 � Xoe�Ve⁄EPV (2)
here X1 equals the final plasma concentration,o equals the initial concentration, and Ve equals
he volume exchanged. (Of interest to nephrolo-ists, the relation shown on this graph and theosttreatment percentage of reduction is exactlynalogous to the Kt/V calculations associatedith urea reduction ratios during dialysis inhich Ve is Kt and EPV is V). The relation islotted in Fig 1.Extravascular to intravascular reequilibration
f a large-molecular-weight substance will beelatively slow (�1% to 3% per hour). Thus,everal consecutive treatments separated by 24o 48 hours each will have to be performed toemove a substantial percentage of the total-bodyurden. An example of the progressive reductionn serum levels of an immunoglobulin is shown
n Fig 2, with a net 70% decrease in total-bodygG level 1 day after 3 consecutive TPE treat-ents equaling 1 plasma volume each. In gen-
ral, if production rates (resynthesis) are modestie, slowly forming antibody), at least 5 separatereatments during a 7- to 10-day period will beequired to remove 90% of the patient’s initialotal-body burden. If production rates are highie, rapidly forming antibody, complement com-onents), additional treatments may be required.The results shown in Fig 2 describe a best-case
cenario concerning immunoglobulin removal.n some autoimmune diseases, the rate of autoan-ibody production may greatly exceed that of theotal immunoglobulin class. Such has been docu-ented for certain cases of Goodpasture syn-
rome in which anti-GBM activity will be predict-bly decreased by a given plasma exchangereatment, but for which the intertreatment in-reases in serum levels are too rapid to be com-atible with a simple reequilibration of extravas-ular stores. Thus, a 70% absolute decrease in aathogenic autoantibody requires at least 3 plasmaxchange treatments and may require a far morentensive treatment schedule if production ratesannot be adequately controlled by the concomi-ant immunosuppressive medications.
Production rates (half-lives), moleculareights, and percentages of intravascular distri-ution of several serum proteins are listed inable 4.
GENERAL GUIDELINES FOR TPEPRESCRIPTION: SUGGESTED READING
Kaplan AA: A simple and accurate method for prescrib-ng plasma exchange. Trans Am Soc Artif Intern Organs6:M597-M599, 1990
Kaplan AA: Towards a rational prescription of plasmaxchange: The kinetics of immunoglobulin removal. Seminial 5:227-229, 1992
TECHNIQUE
Traditionally, plasma exchange was performedith centrifugation devices used in blood-bank-
ng procedures. These devices offer the advan-age of allowing for selective cell removal (cyta-heresis). Plasma exchange also can be performedsing a highly permeable filter and standardialysis equipment.
I. CentrifugationCentrifugation separates the plasma by
density gradients.Whole-blood constitu-
pirepuedvpmcdP
(cIct
Core Curriculum in Nephrology 1189
ents are layered into plasma (specific grav-ity [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’scellular components can also be accom-plished by filtration though a highly perme-able membrane. Blood is separated into itscellular and noncellular components bysubjecting it to sieving through a mem-brane with pores that allow plasma pro-teins to pass, but that retain the largercellular elements within the blood path.
III. TPE With Dialysis EquipmentTPE can be performed with a highly
permeable filter connected to the bloodpump and pressure monitoring system ofthe dialysis machine. The machine is usedin its “isolated” ultrafiltration mode, by-passing the dialysate proportioning sys-tem.
IV. AnticoagulationFor centrifugal techniques, anticoagla-
Figure 1. Relation of volume exchanged, estimatedlasma volume (EPV), and percentage of decrease in
nitial concentration for large-molecular-weight substancesemoved during therapeutic plasma exchange (TPE). Forxample, if the volume exchanged (Ve) is equal to theatient’s EPV, Ve/EPV will equal 1 and pretreatment val-es will be decreased by 63%. If the plasma exchanged isqual to 1.4 times the EPV, pretreatment levels will beecreased by 75%. As shown in the figure, increasinglyoluminous exchanges during a single treatment yield arogressively smaller decrease in pretreatment levels. Forost indications, each treatment should provide an ex-
hange volume equal to 1 to 1.4 times the EPV. (Repro-uced from Kaplan AA: A Practical Guide to Therapeuticlasma Exchange, copyright Andre Kaplan)
tion is often provided by citrate. For MPSdP
with dialysis equipment, heparin can beused as during standard dialysis.
VII. Replacement Fluids:A. Albumin
Pros: no viral transmission, allergiesare rare
Cons: depletion coagulopathy, im-munoglobulin depletion1. Electrolyte composition
Sodium, 145 � 15 mEq/L; potas-sium, less than 2 mEq/L (sodiumand potassium in mEq/L is equiva-lent to sodium and potassium inmmol/L)
2. Anaphylactic reactionsRare, antibodies to polymerized
albumin?3. “Depletion coagulopathy”
Replacement with albumin willlead to depletion of coagulationfactors.
i. After a single plasma exchange,prothrombin time (PT) increases30%, partial thromboplastin time(PTT) doubles: these increasesoften reverse 1 day after treat-ment
ii. Multiple consecutive treatmentsresult in prolonged increases inPT/PTT
Figure 2. Progressive decrease in immunoglobulin GIgG) levels after 3 consecutive therapeutic plasma ex-hange (TPE) treatments equaling 1 plasma volume each.ntertreatment increases between treatments represent aombination of extravascular to intravascular reequilibra-ion and a variable amount of new IgG synthesis. (Repro-
uced from Kaplan AA: A Practical Guide to Therapeuticlasma Exchange, copyright Andre Kaplan)
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Andre A. Kaplan1190
iii. FFP administered toward theend of the procedure can mini-mize hemorrhagic risks
4. Immunoglobulin depletioni. A single 1-plasma volume ex-
change reduces serum immuno-globulin levels by 60%
ii. Multiple treatments can de-crease immunoglobulin levelsfor several weeks
iii. A single infusion of immuno-globulin (IVIG) administered af-ter a series of TPE treatmentscan reconstitute normal immu-noglobulin levels
5. Risk of viral transmissionAlbumin is heat treated and con-
sidered to be devoid of transmis-sible virus.
Table 4. Distribution and
ProteinConcentration
(mg/mL) MW
ormal physiologyIgG (except IgG3 subclass) 12IgG3 0.7IgMa 0.9IgA 2.5IgD 0.02IgE 0.0001Albumin 45C3 1.4C4 0.5Fibrinogen 3-4Factor VIII 0.1 100Antithrombin III 0.2 56Lipoprotein cholesterol 1.5-2.0 1
athological conditionsMacroglobulinemia, IgM 50-130Bence-Jones protein 4-10 10Endotoxin 3-25 � 10-7 100Immune complexes * �
umor necrosis factor 3-5 � 10-7 50
Note: Values listed are averaged from those reportedreatment will be limited to that which is intravascular. Sueveral consecutive TPE treatments to decrease total bodyave a rapid return to pre-TPE levels unless production rateAbbreviations: MW, molecular weight; TPE, therapeutic pReproduced with permission from: Kaplan AA: A Practialden, MA, 1999, copyright Andre Kaplan.*Highly variable or poorly defined.†Highly dependent on degree of renal function, half-life g‡Half life will be variable and dependent on the clearing c
B. FFP
Pros: Does not lead to postpheresiscoagulopathy or immunoglobulindepletion. FFP is essential for the treat-ment of TTP.
Cons: Anaphylactoid reactions, ci-trate toxicity, small risk of viral trans-mission.1. Anaphylactoid reactions
i. Fever, rigors, urticaria, wheez-ing, hypotension, and laryngealedema
ii. Angiotensin-converting enzyme(ACE) inhibitors should beavoided given their ability toinhibit kinin metabolism
iii. Consider pretreatment with di-phenhydramine intravenously(IV): 0.3 to 0.5 mL of epineph-rine (1:1,000 solution) should
olism of Plasma Proteins
Intravascular(%)
Fractional TurnoverRate (%/d)
Half-life(d)
45 7 2264 17 778 19 542 25 675 37 2.845 94 2.544 11 1767 41 266 43 281 24 4.271 150 0.645 55 2.4
�90 3-5
89 25* 5.9�50 † †
* �50 ‡ ‡�50 ‡ ‡�50 6-20 min
literature. Removal of a substance during a single TPEes with substantial extravascular distribution will requiren. Substances with short half-lives (high turnover rate) willbe slowed by concomitant therapy.exchange; IgG, immunoglobulin G.de to Therapeutic Plasma Exchange. Blackwell Science,
ncreased with renal failure.ties of the reticuloendothelial system.
Metab
� 103 d
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Core Curriculum in Nephrology 1191
administration for severe re-actions
2. Citrate toxicityFFP contains 14% citrate by vol-
ume; can lead to hypocalcemia andmetabolic 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 immuno-deficiency virus (HIV), and 1/641,000units for human T-lymphotrophic vi-rus
3 L of FFP is obtained from 10 to15 donors (15 separate units).
C. Starch replacement for TPESimilar attributes with albumin, may
be less expensive.III. Vascular Access
A. Antecubital veins:1. Ideal for low-flow treatments2. Increasingly difficult to use after
multiple puncturesB. Temporary vascular catheters:
Catheter removal may be hazardousafter an intensive run of TPE treat-ments, which can result in depletioncoagulopathy and increased PT/PTT.1. Femoral vein cannulation2. Subclavian and internal jugular cath-
eters3. Tunneled jugular venous catheters
C. Permanent arteriovenous access:Preferred if treatments are to be
repeated regularly (hyperlipidemia).1. Primary arteriovenous fistula2. Arteriovenous graft
IX. Selective Plasmapheresis TechniquesA. Designed to remove a particular patho-
genic substanceB. Decreases need for replacement fluidC. Minimizes risks of depletion coagu-
lopathy and hypogammaglobulinemiaD. Many systems available in Japan and
Europe, few in United States1. Cascade filtration (“double filtra-
tion”)i. Separated plasma is refiltered
through a secondary filter with
smaller pore sizeii. Larger, unwanted molecules re-moved by secondary filter
iii. Indications: Waldenstrom mac-roglobulinemia, cryoglobuline-mia, familial hypercholesterol-emia, and immune complex–mediated disease
2. Cryofiltrationi. Removed plasma is cooled,
causing certain substances toaggregate
ii. Increasing size allows for effi-cient secondary filtration
iii. Indications: cyroglobulins andimmune complexes
3. Immunoadsorbant techniquesi. Systems for selective immuno-
adsorptionii. Indications: nonselective immu-
noglobulin removal, low- den-sity lipoprotein (LDL) choles-terol.a. Protein A columns
ProteinA: 42,000-d proteinreleased from Staphylococcusaureus. Used for the ex vivoadsorption of 3 of the 4 classesof IgG (1, 2, and 4).aa. Prosorba column (Cy-
press Biosciences Inc,San Diego, CA)
Single-use nonregener-ating system placed in se-ries with a standardplasma exchange circuit.When the plasma is sepa-rated from the blood, it isslowly perfused over thecolumn (at 20 mL/min).This column saturates rap-idly with very limited IgGremoval. Postulated modeof action is by “immuno-modulation” of perfusedplasma.
Food and Drug Ad-ministration approvedfor idiopathic thrombo-cytopenic purpura (ITP)and rheumatoid arthritis.
Secondary effects are
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Andre A. Kaplan1192
common: fever, chills,musculoskeletal pains,hypotension. Contraindi-cated in patients usingACE inhibitors.
bb. Excorim (Lund, Swe-den)
Alternating columnsrepeatedly regenerated toallow for more efficientIgG removal
Renal indications: re-moval of anti-HLA anti-bodies in highly sensi-tized recipients, RPGN
4. Selective LDL cholesterol removali. Limits the loss of plasma pro-
teins and high-density lipopro-tein (HDL) cholesterol
ii. Indicated in patients with famil-ial hypercholesterolemia whocannot tolerate or whose condi-tion is unresponsive to pharma-cological treatment and whohave either known cardiovascu-lar disease and a plasma LDLcholesterol level greater than200 mg/dL or no known cardio-vascular disease and a plasmaLDL cholesterol level greaterthan 300 mg/dL
iii. Four systems:a. Imunoadsorbantb. Dextran sulfate binding to
apoprotein BContraindication for pa-
tients on ACE-inhibitortherapy
c. Heparin-mediated extracor-poral LDL precipitation(HELP)
d. Direct adsorption of LDL(DALI). Does not requireplasma separation, removesLDL directly from wholeblood
5. Endotoxin adsorptioni. Fibers impregnated with poly-
myxin B. Can bind endotoxin
fragments bii. Japanese experience documentsimprovement in systemic hemo-dynamics of sepsis
iii. Not currently available in theUnited States
TECHNIQUE: SUGGESTED READINGS
Gurland HJ, Lysaght MJ, Samtleben W, Schmidt B: Aomparison of centrifugal and membrane based apheresisormats. Int J Artif Organs 7:35-38, 1984
entrifugation:
Sowada K, Malchesky PS, Nose Y: Available removalystems: State of the art, in Nydegger UE (ed): Therapeuticemapheresis in the 1990s. Curr Stud Hematol Blood Transf7:51-113, 1990
embrane Plasma Separation:
Gurland HJ, Lysaght MJ, Samtleben W, Schmidt B:omparative evaluation of filters used in membrane plasma-heresis. Nephron 36:173-182, 1984
Sueoka A: Present status of apheresis technologies: Part. Membrane plasma separator. Ther Apher 1:42-48, 1997
PE With Dialysis Equipment:
Gerhardt RE, Ntoso KA, Koethe JD, Lodge S, Wolf CJ:cute plasma separation with hemodialysis equipment. J Amoc Nephrol 2:1455-1458, 1992
Price CA, McCarley PB: Technical considerations ofherapeutic plasma exchange as a nephrology nursing proce-ure. ANNA J 20:41-46, 1993
itrate Anticoagulation:
Hester JP, McCullough J, Mishler JM, Szymanski IO:osage regimens for citrate anticoagulants. J Clin Apher:149-157, 1983
eplacement Fluids: Albumin:
Finlayson JS: Albumin products. Semin Thromb Hemost:85-120, 1980
eplacement Fluids: FFP:
AuBuchon JP, Birkmeyer JD, Busch MP: Safety of thelood supply in the United States: Opportunities and contro-ersies. Ann Intern Med 127:904-909, 1997
eplacement Fluids: Starch:
Brecher ME, Owen HG, Bandarenko N: Alternatives tolbumin: Starch replacement for plasma exchange. J Clinpher 12:146-153, 1997
ascular Access:
Mokrzycki MH, Zhang M, Golestaneh L, Laut J, Rosen-
erg SO: An interventional controlled trial comparing 2
mcu5
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Core Curriculum in Nephrology 1193
anagement models for the treatment of tunneled cuffedatheter bacteremia: A collaborative team model versussual physician-managed care. Am J Kidney Dis 48:587-95, 2006
ascade Filtration Double Filtration:
Agishi T, Kaneko I, Hasuo Y, et al: Double filtrationlasmapheresis. Trans Am Soc Artif Intern Organs 26:406-09, 1980
elective Plasmapheresis Techniques:
Malchesky PS, Kaplan AA, Coo AP, Sadurada Y, SiamiA: Are selective macromolecule removal plasmapheresis
ystems useful for autoimmune diseases or hyperlipidemia?SAIO J 39:868-872, 1993
ryofiltration:
Vibert GJ, Wirtz SA, Smith JW, et al: Cryofiltration as anlternative to plasma exchange: Plasma macromolecularolute removal without replacement fluids, in Nose Y, Mal-hesky PS, Smith JW (eds): Plasmapheresis. Cleveland, OH,SAO, 1983, pp 281-287
rotein A Columns:
Samtleben W, Schmidt B, Gurland HJ: Ex vivo and inivo protein A perfusion: Background, basic investigationsnd first clinical experience. Blood Purif 5:179-192, 1987
rosorba Column:
Brecher ME, Owen Hg, Collins ML: Apheresis and ACEnhibitors. Transfusion 33:963-964, 1993 (letter)
Feldon DT, LeValley MP, Baldassare AR, et al. Therosorba column for treatment of refractory rheumatoidrthritis. A randomized, double blind, sham controlled trial.rthritis Rheum 42:2153-2159, 1999
xcorim:
Hakim RM, Milford E, Himmelfarb J, Wingard R, Laza-us JM, Watt RM: Extracorporeal removal of anti-HLAntibodies in transplant candidates. Am J Kidney Dis 16:423-31, 1990
Ross CN, Gaskin G, Gregor-Macgregor S, et al: Renalransplantation following immunoadsorption in highly sensi-ized recipients. Transplantation 55:785-789, 1993
elective Lipid Removal:
Saal SD, Parker TS, Gordon BR: Removal of low-densityipoproteins in patients by extracorporeal immunoadsorp-ion. Am J Med 80:583-589, 1986
Gordon BR, Kelsey SF, Bilheimer DW, et al: Treatmentf refractory familial hypercholesterolemia by low densityipoprotein apheresis using an automated dextran sulfateellulose adsorption system. Am J Cardiol 70:1010-1016,
992Busnach G, Cappelleri A, Vaccarino V, et al: Selectivend semiselective low-density lipoprotein apheresis in famil-al hypercholesterolemia. Blood Purif 6:156-161, 1988
Kroon AA, van Asten WNJC, Stalenhoef AFH: Effect ofpheresis of low-density lipoprotein on peripheral vascularisease in hypercholesterolemic patients with coronary ar-ery disease. Ann Intern Med 125:945-954, 1996
Jovin IS, Taborski U, Stehr A, Müller-Berghaus G: Lipideductions by low-density lipoprotein apheresis: A compari-on of three systems. Metabolism 49:1431-1433, 2000
Bosch T, Gahr S, Belschner U, Schaefer C, Lennertz A,ammo J, for the DALI Study Group: Direct adsorption of
ow-density lipoprotein by DALI-LDL-apheresis: Results ofprospective long-term multicenter follow-up covering
2,291 sessions. Ther Apher Dial 10: 210-218, 2006
ndotoxin Adsorption:
Aoki H, Kodama M, Tani T, Hanasawa K: Treatment ofepsis by extracorporeal elimination of endotoxin usingolymyxin B-immobilized fiber. Am J Surg 167:412-417,994
COMPLICATIONS
Most common: citrate-induced parethesias,uscle cramps, urticaria (Table 5).Most serious: anaphylactoid reactions to FFPIncidence of death is 0.05%, but many patients
ave severe preexisting conditions
I. Citrate-Induced HypocalcemiaA. Citrate as anticoagulant or in FFPB. Perioral or distal extremity tingling or
paresthesiasC. Prophylactic replacement of IV cal-
cium can reduce citrate-inducedparesthesias
II. Coagulation AbnormalitiesA. Depletion coagulopathy
1. After a single plasma exchangewith albumin, clotting factors de-crease by 60%
2. When multiple treatments are per-formed, depletion more pronounced
D. ThrombocytopeniaE. Anemia: hemorrhage associated with
vascular access, treatment-related he-molysis
F. Thrombosis: hypercoaguable state fromdepletion of anticoagulant factors
III. InfectionA. Resulting from posttreatment deple-
tion of immunoglobulinsManagement: IVIG (100 to 400
mg/kg IV)
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Andre A. Kaplan1194
B. Viral transmission from replacementfluid (FFP)
IV. Reactions to Protein Containing Replace-ment Fluids (FFP, purified protein fraction,albumin)
Reactions to FFP are anaphylactoid innature and characterized by fever, rigors,urticaria, wheezing, and hypotension andmay eventually progress to laryngospasm.
V. Atypical Reactions Associated With ACEInhibitors
Flushing, hypotension, abdominal cramp-ing, and severe anaplylactoid reactions havebeen reported with the dextran sulfate sys-tems for selective lipid removal and inpatients treated with the Prosorba column.Concurrent treatment with ACE inhibitors isconsidered contraindicated in patients treated
Table 5. Complications of Plasmapheresis
Symptom Percentage
rticaria 0.7-12aresthesias 1.5-9uscle cramps 0.4-2.5izziness �2.5eadaches 0.3-5ausea 0.1-1ypotension 0.4-4.2hest pain 0.03-1.3rrhythmia 0.1-0.7naphylactoid reactions 0.03-0.7igors 1.1-8.8yperthermia 0.7-1.0ronchospasm 0.1-0.4eizure 0.03-0.4espiratory arrest/pulmonary edema 0.2-0.3yocardial ischemia 0.1hock/myocardial infarction 0.1-1.5etabolic alkalosis 0.03isseminated intravascular coagulation 0.03entral nervous system ischemia 0.03-0.1epatitis 0.7emorrhage 0.2ypoxemia 0.1ulmonary embolism 0.1ccess relatedThrombosis/hemorrhage 0.02-0.7Infection 0.3Pneumothorax 0.1Mechanical 0.08-4
Adapted from Mokrzycki and Kaplan, Am J Kidney Dis3:817, 1994. Reproduced from: Kaplan AA: A Practicaluide to Therapeutic Plasma Exchange. Blackwell Sci-nce, Malden, MA, 1999, copyright Andre Kaplan
with these selective removal techniques.
ACE-inhibitor–induced inhibition of kininmetabolism may be unifying factor. Discon-tinuation ofACE inhibition should be accom-plished well before initiation of these treat-ments. Timing of this discontinuation willdepend on individual ACE-inhibitor half-lifeand pharmacodynamics.
VI. Electrolyte AbnormalitiesA. Hypokalemia: albumin has potassium
levels less than 2 mEq/LB. Alkalosis: from citrate used for antico-
agulation or in FFPC. Aluminum: albumin solutions have 4
to 24 mmol/L of aluminumRisk of aluminum toxicity greatest
with renal insufficiencyVII. Vitamin Removal
A. Vitamins B12, B6, A, C, and E and�-carotene decrease of 24% to 48%,but there is a rebound to pretreatmentlevels within 24 hours
B. Water-soluble vitamins, folate, thia-min, nicotinate, biotin, riboflavin, andpantothenate are not significantly al-tered by a single plasma exchange
C. Long-term effects of repetitive treat-ments are not known
III. Miscellaneous ComplicationsA. Apneic events in those anesthetized with
succinylcholine due to low posttreatmentlevels of plasma cholinesterase
B. Hypotension, dyspnea, and chest painsecondary to complement-mediatedmembrane bioincompatibility
C. Anaphylactoid symptoms due to ethyl-ene oxide sensitivity used as a steriliz-ing agent
D. Severe hemolysis as a result of hypo-tonic priming solutions or aggressivetransmembrane pressure during MPS
E. Chills and hypothermia due to inad-equately warmed replacement fluid
IX. Hypotension During TPEA. Incidence of hypotension is 1.7%B. Causes: see Table 6
X. DeathsA. Incidence of 0.05%B. Causes: cardiovascular, respiratory, and
anaphylactici. Nonhemodynamic pulmonary edema
(FFP replacement resulting in
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Core Curriculum in Nephrology 1195
transfusion-related lung injury[TRALI])
ii. Cardiac arrhythmiaiii. Hemodynamic pulmonary edemaiv. Pulmonary embolism
XI. Drug RemovalWhen possible, all daily drug dosing
should be administered after the TPE treat-ment.
Drug removal is most dependent onpercentage of protein binding and volumeof distribution. Drugs with a high percent-age of protein binding and a relativelymodest volume of distribution (�0.3 L/kg)will have the greatest likelihood of beingremoved by TPE (Table 7). The replace-ment volume of a given TPE treatment
Table 6. Potential Causes for HypotensionDuring TPE
elayed or inadequate volume replacementasovagal episodesypo-oncotic fluid replacement: 3.5% albumin solutionsnaphylaxis:Reactions to plasma components in replacement fluidsAnti-IgA antibodies (IgA-deficient patient)Endotoxin-contaminated replacement fluidReactions to bioincompatible membranesSensitivity to ethylene oxideDevice-related: Prosorba protein A column
ardiac arrhythmiaCitrate-induced hypocalcemiaHypokalemic related (especially in patients on digitalis
therapy)radykinnin reactions (cf reactions to ACE inhibitors)emorrhageAssociated with primary disease (ITP, factor VIII
inhibitors)Associated with heparin anticoagulationAssociated with vascular accessExternalInternal“Depletion” coagulopathy
ardiovascular collapseulmonary embolusisease-related hypotensionGuillain-Barre syndrome (autonomic dysfunction)Waldenstrom macroglobulinemia (rapid decrease in
plasma volume)
Abbreviations: IgA, immunoglobulin A; ACE, angiotensin-onverting enzyme; ITP, idiopathic thrombocytopenic pur-ura; TPE, therapeutic plasma exchange.Reproduced from: Kaplan AA: A Practical Guide to
herapeutic Plasma Exchange. Blackwell Science, Mal-en, MA, 1999, copyright Andre Kaplan.
would have to equal 0.7 times the volume d
of distribution of a drug to decrease pre-treatment levels by 50%.A. Specific drugs:
1. Not significantly removed by TPE:i. Prednisone
ii. Prednisolone2. Minimal removal:
i. Cyclophosphamideii. Azathioprine
iii. Aminoglycosidesiv. Tobramycinv. Digoxin (removal of digibind-
bound drug may be enhancedin patients with renal failure)
vi. Digitoxinvii. Vancomycin
3. Posttreatment supplement may benecessary:
i. Phenytoinii. Acetylsalicylic acid
iii. Propranololiv. Thyroxine: 25% in the intra-
vascular compartment 99%
Table 7. Drugs With a High Percentage of ProteinBinding and Modest Volume of Distribution
ProteinBinding (%)
Volume ofDistribution
(L/kg)
cetylsalicylic acid 50-90 0.1-0.2efazolin 80 0.13-0.22efotetan 85 0.15eftriaxone 90 0.12-0.18hlorpropamide 72-96 0.09-0.27iclofenac �99 0.12-0.17icloxacillin 95 0.16lyburide 99 0.16-0.3eparin �90 0.06-0.1
buprofen 99 0.15-0.17ndomethacin 99 0.12etorolac �99 0.13-0.25aproxen 99 0.10robenecid 85-95 0.15odium valproate 90 0.19-0.23treptokinase ? 0.02-0.08olbutamide 95-97 0.10-0.15arfarin 97-99 0.11-0.15
Note: In general, drugs with a high percentage of proteininding and a modest volume of distribution are likely to beemoved by plasma exchange.
Reproduced from: Kaplan AA: A Practical Guide toherapeutic Plasma Exchange. Blackwell Science, Mal-
en, MA, 1999, copyright Andre Kaplan.
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protein bound: TPE can treatthyroid storm
COMPLICATIONS: SUGGESTED READINGS
Sutton DMC, Nair RC, Rock G, and the CanadianAphere-is Study Group: Complications of plasma exchange. Trans-usion 29:124-127, 1989
Mokrzycki MF, Kaplan AA: Therapeutic plasma ex-hange: Complications and management. Am J Kidney Dis3:817-827, 1994
itrate-Induced Hypocalcemia:
Silberstein LE, Naryshkin S, Haddad JJ, Strauss JF:alcium homeostasis during therapeutic plasma exchange.ransfusion 26:151-155, 1986
oagulation Abnormalities:
Wood L, Jacobs P: The effect of serial therapeutic plasma-heresis on platelet count, coagulation factors plasma immu-oglobulin and complement levels. J Clin Apher 3:124-128,986
Sultan Y, Bussel A, Maisonneuve P, Sitty X, Gajdos P:otential danger of thrombosis after plasma exchange in the
reatment of patients with immune disease. Transfusion9:588-593, 1979
nfection:
Pohl MA, Lan SP, Berl T, and the Lupus Nephritisollaborative Study Group: Plasmapheresis does not in-rease the risk for infection in immunosuppressed patientsith severe lupus nephritis. Ann Intern Med 114:924-929,991
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ: Theisk of transfusion-transmitted virus invections. The Retrovi-us Epidemiology Donor Study. N Engl J Med 334:1685-690, 1996
eactions to Protein-Containing Solutions:
Apter AJ, Kaplan AA: An approach to immunologiceactions with plasma exchange. J Allergy Clin Immunol
0:119-124, 1992 dtypical Reactions to ACE Inhibitors:
Owen HG, Brecher ME: Atypical reactions associatedith use of angiotensin-converting enzyme inhibitors and
pheresis. Transfusion 34:891-894, 1994Olbricht CJ, Schauman D, Fisher D: Anaphylactoid reac-
ions, LDL apheresis with dextran sulfate and ACE inhibi-ors. Lancet 3:340:908-909, 1992
lectrolyte Abnormalities:
Pearl RG, Rosenthal MH: Metabolic alkalosis due tolasmapheresis. Am J Med 79:391-393, 1985
Milliner DS, Shinaberger JH, Shurman P, Coburn JW:nadvertent aluminum administration during plasma ex-hange due to aluminum contamination of albumin replace-ent solutions. N Engl J Med 312:165-167, 1985
itamin Removal:
Reddi A, Frank O, DeAngelis B, et al: Vitamin status inatients undergoing single or multiple plasmapheresis. J Amoll Nutr 6:485-489, 1987
iscellaneous Complications:
MacDonald R, Robinson A: Suxamethonium apnea asso-iated with plasmapheresis. Anaesthesia 35:198-201, 1980
Jorstad S: Biocompatibility of different hemodialysis andlasmapheresis membranes. Blood Purif 5:123-137, 1987
Nicholls AJ, Platts MM: Anaphylactoid reactions due toaemodialysis, haemofiltration or membrane plasma separa-ion. Br Med J 285:1607-1609, 1982
eaths:
Huestis DW: Mortality in therapeutic haemapheresis.ancet 1:1043, 1983 (letter)
rug Removal:
Jones JV: The effect of plasmapheresis on therapeutic
rugs. Dial Transplant 14:225-226, 1985