Therapeutic Plasma Exchange: Core Curriculum 2008

Abstract

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. 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. Cohen S, Freeman T: Metabolic heterogeneity of human gamma globulin. Biochem J 76:475-487, 1960 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:IStandard therapy, acceptable but not mandatoryIIAvailable evidence tends to favor efficacy: conventional therapy usually tried firstIIIInadequately tested at this timeIVNo 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 1Indications for TPEReference1American Medical Association Council on Scientific AffairsCurrent status of therapeutic plasmapheresis.JAMA. 1985; 253: 819-825Crossref PubMed Scopus (60) Google Scholar2Strauss R.G. Ciavarella D. Gilcher R.O. et al.An overview of current management.J Clin Apher. 1993; 8: 189-194Crossref PubMed Scopus (62) Google Scholar3Leitman S.F. Ciavarella D. McLeod B. Owen H. Price T. Sniecinski I. Guidelines for Therapeutic Hemapheresis. American Association of Blood Banks, Bathesda, MD1994Google Scholar4Therapeutics and Technology Assessment Subcommittee of the American Academy of NeurologyAssessment of plasmapheresis Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.Neurology. 1996; 47: 840-843Crossref PubMed Scopus (78) Google Scholar5Szczepiorkowski Z.M. Bandarenko N. Kim H.C. 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: 106-175Crossref PubMed Scopus (203) Google ScholarYear19861993199419962007RatingRatingRatingRatingRatingNeurological diseases Guillain-Barre syndromeIIIestI Myasthenia gravisIIIestI Chronic inflammatory demyelinating polyneuropathyIIIIIestI Paraprotein-associated polyneuropathynlIInlestI-III Multiple sclerosisIIIIIIIIposII-III Eaton Lambert syndromenlInlposII Stiff man syndromenlnlnlinvestIII Amyotrophic lateral sclerosisIVIVIVnlnl Neuromyotonianlnlnlinvestnl Acute disseminated encephalomyelitisnlnlnlinvestIII Refsum's diseasenlInlinvestII Sensorineural hearing lossnlnlnlnlnlHematologic disorders Hyperviscosity syndromeIIII CryoglobulinemiaIIIII Thrombotic thrombocytopenic purpuraIIII Hemolytic uremic syndromenlIIIIIII-IV Idiopathic thrombocytopenic purpuraIIIIIIIIIII-IV Posttransfusion purpuraIIIIIII Autoimmune hemolytic anemiaIIIIIIIIIIII Maternal-fetal incompatibility-Rh diseaseIIIIInlII Removal of factor VIII inhibitorsIIIIIIIIIIMetabolic disorders HypercholesterolemiaIII-IIII-II HypertriglyceridemianlnlnlIII Pruritis associated with cholestasisIInlnlnl Hepatic failureIIIIIInlIII Graves' disease and thyroid stormIIIIIIIIII Insulin receptor antibodiesnlnlnlnlDermatological disorders Pemphigus vulgarisIIIIInlIII Bullous pemphigusnlIInlnl Toxic epidermal necrolysis (Lyell syndrome)nlnlnlnl Porphyria cutanea tardanlnlnlnl PsoriasisIIIIVIVnlRheumatological disorders Systemic lupus erythematosusIIIInlIII-IV Antiphospholipid syndrome/(lupus anticoagulant)nlnlnlIII SclerodermaIIIIIIIIIIII Rheumatoid arthritis/rheumatoid vasculitisIIIIIIV&IIII VasculitisIIIIIInl Polymyositis/dermatomyositisIIIIII/IVIVnlRenal disease Goodpasture syndromeIIII Rapidly progressive glomerulonephritisIIIIIIII Multiple myeloma, cast nephropathyIIIInlIII Henoch-Schönlein purpura/IgA nephropathyIInlnlnl Focal segmental glomerulosclerosis Recurrence posttransplantationnlnlnlIII Renal allograft rejectionIIIVIVII Removal of cytotoxic antibodies in the transplant candidatenlnlnlIIIndications for TPE in the ICU Fulminant systemic meningococcemianlnlnlnl EndotoxemianlnlnlIII Burn shockIIInlnlnl Human immunodeficiency virusIIInlnlnl Immune thrombocytopenic purpuranlIInlnl Thrombotic thrombocytopenic purpuranlInlnl Peripheral neuropathynlInlnlIntoxicationsIIIIIII-III Arsine Carbamazepine Cisplatin Digitoxin Digoxin Diltiazem Mushroom poisoningIIII ParaquatII ParathionII Phenylbutazone Phenytoin Quinine Sodium chlorateII Theophylline Thyroxine Tricyclic antidepressant VincristineNote: 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. Open table in a new tab 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 2Medicare Reimburseable Indications for Plasma Exchange⁎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.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 deteriorationNote: 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. Open table in a new tab Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. 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.IAnti–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.ATreatment strategy:1Early initiation of TPE is essential to avoid ESRD2Initial prescription is 14 daily 4-L exchanges3Continued apheresis may be required if antibody titers remain increased4Steroids, cyclophosphamide, or azathioprine are added to decrease production of anti-GBM antibody and minimize the inflammatory responseIICrescentic 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 3Controlled Trials of TPE for Patients With Severe or Dialysis-Dependent Rapidly Progressive GlomerulonephritisReferenceIndex of severityTPEno TPEMauri et al,1Mauri J.M. Gonzales M.T. Poveda R. et al.Therapeutic plasma exchange in the treatment of rapidly progressive glomerulonephritis.Plasma Ther Transfus Technol. 1985; 6: 587-591Google Scholar 1985Creatinine > 9 mg/dL Initial creatinine, mg/dL (no. of patients)13.5 (6)13.1 (5) Creatinine after 3 y (mg/dL)8.7⁎P < 0.05 with day 0.13.4Glockner et al,2Glockner W.M. Sieberth H.G. Wichmann H.E. et al.Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: A controlled multi-center study.Clin Nephrol. 1988; 29: 1-8PubMed Google Scholar 1988Dialysis dependent Initial creatinine, mg/dL (no. of patients)7.4 (8)9.2 (4) Creatinine after 6 mo1.7⁎P < 0.05 with day 0.5.5Pusey et al,3Pusey C.D. Rees A.J. Evans D.J. Peters D.K. Lockwood C.M.L. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies.Kidney Int. 1991; 40: 757-763Crossref PubMed Scopus (316) Google Scholar 1991Dialysis dependent Initial no. of patients on dialysis118 Patients off dialysis at 12 mo10†P < 0.05, TPE versus no TPE.3Cole et al,4Cole E. Cattran D. Magil A. et al.Canadian Apheresis Study GroupA prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis.Am J Kidney Dis. 1992; 20: 261-269PubMed Scopus (136) Google Scholar 1992Dialysis dependent Initial no. of patients on dialysis47 Patients off dialysis at 12 mo32Jayne et al,5Jayne D.R. Gaskin G. Rasmussen N. et al.European Vasculitis Study GroupRandomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis.J Am Soc Nephrol. 2007; 18: 2180-2188Crossref PubMed Scopus (792) Google Scholar 2007Creatinine > 5.8 mg/dL Initial no. of patients7067 Patients off dialysis at 12 mo5740Note: 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. Open table in a new tab 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.IIIRenal 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).ATreatment considerations:1Demonstration 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)2Successful TPE prescription is 3 to 4 L of plasma exchanged on 5 consecutive days3Well-established (chronic) renal failure considered to be caused by cast nephropathy may respond less dramatically4Newly available highly permeable hemofilter membranes may allow for light chain removal without significant albumin loss (Hutchison et al)IVIgA Nephropathy and Henoch-Schönlein PurpuraCase reports and small clinical series suggest a possible beneficial effect of TPE in the treatment of IgA-associated RPGN.VCryoglobulinemiaDespite 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.ATreatment strategy:1A reasonable TPE prescription is to exchange 1 plasma volume 3 times weekly for 2 to 3 weeks2An average of 13 treatments may be required to induce clinical improvement (range, 4 to 39)3The replacement fluid can be 5% albumin, which must be warmed to prevent precipitation of circulating cryoglobulinsVITTP and Hemolytic Uremic Syndrome (HUS)ATTPA 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.1Treatment considerations:iFFP is required as replacement fluid to replace missing metalloprotease (ADAMTS13 [A Disintigrin-like And Metalloprotease with ThromboSpondin type 1 repeats])iiPlasma removal with TPE removes antibody to ADAMTS13iiiTreatments are performed daily until the platelet count is normalized and hemolysis has largely ceased (normalization of lactate dehydrogenase)ivExchanged volumes should be at least 1 plasma volume. Some experts recommend 1.5 plasma volume exchanges for the first weekvPrevious 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)BHUS in adultsAlthough renal failure tends to dominate the clinical presentation, unless a specific cause can be identified, HUS is often difficult to distinguish from TTP1Causes:iVerotoxin induced by Escherichia coli 0157-H7: prodrome of bloody diarrheaiiDrugs: cyclosporine, tacrolimus, mitomycin, cisplatinum, quinine, oral contraceptives, antiplatelet agents, and so oniiiLupusivCancervBone marrow transplantviiPosttransplantation recurrence2Prognosis in adults is poor:iMortality between 25% and 50%iiESRD in 40%Although treatment success depends on the cause, HUS in adults is often treated with TPE as with TTP.CHUS 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:1Without a diarrheal prodrome2Older than 5 years3With significant central nervous system involvementVIISystemic 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:APregnancy, when cytotoxic agents are undesirableBLupus-associated TTPCLupus anticoagulant (LA)/antiphospholipid antibody syndromeVIIILA, 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).IXSclerodermaTPE may be useful in rare coexistence of scleroderma and ANCA-positive or antinuclear antibody (ANA)-positive renal disease.XFocal 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.XIITransplant 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.XIIIRenal 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.XIVRenal 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. 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. 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 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 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 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 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 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 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 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 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 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 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) 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 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 Ross CN, Gaskin G, Gregor-Macgregor S, et al: Renal transplantation following immunoadsorption in highly sensitized recipients. Transplantation 55:785-789, 1993 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 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 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:EPV=(0.065×weight [kg])×(1−hematocrit)(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:X1=Xoe−Ve/EPV(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. 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. The results shown in Fig 2 describe a best-case scenario con