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The Rationale for Therapeutic Plasma Exchange

The Rationale for Therapeutic Plasma Exchange. Stuart L. Goldstein, MD Professor of Pediatrics Baylor College of Medicine Medical Director, Renal Dialysis and Pheresis Service Texas Children’s Hospital Houston, Texas. Outline. Principles of TPE Centrifugal TPE Membrane TPE

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The Rationale for Therapeutic Plasma Exchange

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  1. The Rationale for Therapeutic Plasma Exchange Stuart L. Goldstein, MD Professor of Pediatrics Baylor College of Medicine Medical Director, Renal Dialysis and Pheresis Service Texas Children’s Hospital Houston, Texas

  2. Outline • Principles of TPE • Centrifugal TPE • Membrane TPE • What rationale exists for TPE? • When should TPE be considered • AABB, ASFA classifications • Specific disease entities

  3. Membrane vs. Centrifugation • In the US, most TPE is performed by centrifugation.  One machine can do all apheresis procedures. • Double filtration method: first membrane separates plasma from cellular portion and second membrane separates globulin from albumin.

  4. Plasma Platelets Lymphocytes Monocytes Neocytes Granulocytes Erythrocytes Blood Components Separated by Centrifugation

  5. Plasma Exchange

  6. TPE: Available techniques... TPE: Available techniques • Cascade or secondary filtration: Separated blood is perfused through a plasma filter (1) to remove certain plasma elements. The second column (2) (cascade) absorbs the element and the plasma is returned to the patient. 1 2 PATIENT

  7. Plasma removal is affected by: • Qb • Hct • Pore Size • TMP =Plasma effluent Qb 100-150 Hct 25-45% TMP <50 mmHg Pore Size

  8. Efficiency of removal is greatest early in the procedure and diminishes progressively during the exchange

  9. Plasma Volume Exchange

  10. Small vs. Large Volume Exchange • 1.0 plasma volume exchange: minimizes time required for each procedure but may need more frequent procedures. • 2.0 – 3.0 plasma volume exchange: greater initial diminution of pathologic substance but requiring considerably more time to perform the procedure.

  11. Rationale of Plasma Exchange • The existence of a known pathogenic substance in the plasma. • IgG, IgM, phytanic acid, cytokines (?) • The possibility of removing this substance more rapidly than it can be renewed in the body.

  12. Mechanical Removal of Antibodies • When antibody is rapidly and massively decreased by TPE, antibody synthesis increases rapidly. • This rebound response complicates treatment of autoimmune diseases. • It is usually combined with immune suppressive therapy.

  13. Indication for TPECategory 1: Standard acceptable therapy • Chronic idiopathic demyelinating polyneuropathy (CIDP) • Cryoglobulinemia • Goodpasture syndrome • Guillain-Barre syndrome • Recurrent FSGS • Myasthenia gravis • Post transfusion purpura • Refsum’s disease • TTP

  14. Indication for TPECategory 2: Sufficient evidence to suggest efficacy as adjunctive therapy • ABO incompatible organ transplant • bullous pemphigoid • coagulation factor inhibitors • drug overdose and poisoning (protein bound) • Eaton-Lambert syndrome • HUS • monoclonal gammopathy with neuropathy • Sydenham’s chorea • RPGN • Systemic vasculitis

  15. Indication for TPECategory 3: Inconclusive evidence of efficacy or uncertain risk/benefit ratio. TPE can be considered for the following occasions: • Standard therapies have failed. • Disease is active or progressive. • There is a marker to follow. • It is agreed that it is a trial of TPE and when to stop. • Possibility of no efficacy is understood by the patient.

  16. Indication for TPECategory 4: Lack of efficacy in controlled trials. • Examples: AIDS, amyotrophic lateral sclerosis, lupus nephritis, psoriasis, renal transplant rejection, schizophrenia, rheumatoid arthritis

  17. Thrombotic Syndromes • TTP-HUS complex • Sepsis • Malignancy • Drugs • Pancreatitis • Pregnancy

  18. ADAMTS-13 and vWF the 13th member of a disintegrin and metalloprotease family with thrombospondin domains (ADAMTS-13)

  19. Plasma Exchange and TTP • One major comparative trial • (Rock et al NEJM, 1991) • TPE (centrifugation) vs. FFP infusion • 1.5 volume exchange • Mean 15.8 exchanges • Outcomes • Increased platelets (TPE 40/51 vs. FFP 25/51, p<0.005) • Survival (TPE 40/51 vs. FFP 32/51, p<0.05)

  20. TPE in TTP: Different Replacement Fluids • Concerns raised regarding exposure to large volumes of FFP and inherent infectious risks • Randomized double-blind trial for TTP with FFP vs. photo-chemically treated FFP (Mintz: Transfusion, 2006)

  21. TPE in Sepsis • Significant debate over the risks/benefits of TPE in sepsis and MODS • Could this be of benefit in prothrombotic forms of sepsis and MODS? • The risk of the increased immunosuppressive effect • What parameter to follow?

  22. Asanuma et al: Ther Apher Dial. 2004 • Retrospective review • 33 patients with sepsis and MODS secondary to acute peritonitis • 18 patients with necrotizing pancreatitis • All patients received surgery

  23. Busund: Intens Care Med, 2002 • Proespective randomized trial of standard therapy + TPE in Russia • 106 patients • One TPE treatment followed by another in 24 hours if no clinical improvement noted • Primary end-point was 28 day survival

  24. Busund: Intens Care Med, 2002

  25. Busund: Intens Care Med, 2002

  26. Busund: Intens Care Med, 2002

  27. Busund: Intens Care Med, 2002

  28. Busund: Intens Care Med, 2002

  29. Stegmayr: Crit Care Med, 2003 • Retrospective review of 76 patients with DIC and MODS (at least ARF) who received TPE • 66/76 (83%) with septic shock • Median 2 TPE Rxs (range 1-14) • Outcome was mortality compared to the literature based on similar diagnoses and APACHE II scores

  30. Stegmayr: Crit Care Med, 2003

  31. Pediatric patients (Pittsburgh) • TAMOF • Period 1 • OFI > 2 • Thrombocytopenia (< 100,000) • Period 2 • OFI > 3 • Thrombocytopenia (< 100,000) • AKI (SCr > 1, oliguria)

  32. ULVWF seen in 15/25 patients with decreased ADAMTS-13 activity and TAMOF (technique?) • All four pts with activity <10% had ULVWF (dose effect?) 10 patients (5 in each group)

  33. TPE in Transplantation • Recurrent FSGS • Other recurrent GN • ABO incompatibility • Humoral transplant rejection

  34. FSGS and Renal Transplant: NAPRTCS • FSGS erases LD transplant survival advantage • Reasons for graft failure • Similar ATN incidence • Increased recurrence (FSGS 6.1% vs 0.7%) Baum MA et al: Kid Int 2001 Baum MA et al: Ped Transplant 2002

  35. Increased Recurrence with Higher Permeability Activity Savin V et al: NEJM 1996

  36. TPE Decreases PA: HD Patient Savin V et al: NEJM 1996

  37. TPE Decreases PA and Proteinuria: 6 TX Patients Savin V et al: NEJM 1996

  38. TPE to Treat Recurrent FSGS: Review • No controlled trials • Meta-analysis of case reports and series in 2001 to guide TPE treatment numbers • NAPRTCS does not collect data regarding recurrent FSGS occurrence rates, only if recurrent FSGS was cause of graft failure

  39. TPE for Recurrent FSGS: Meta-Analysis • Inclusion criteria • ESRD secondary to FSGS AND • Renal transplantation AND • Recurrence of FSGS • Nephrotic range proteinuria OR • Biopsy confirmation • TPE provision • Cases with secondary diagnoses included • TPE response • 50% reduction in proteinuria Davenport R: J Clin Apher 2001

  40. Meta-Analysis Results • 44 cases from 12 reports satisfied inclusion criteria • Median time to recurrence was 21 days • Median time from diagnosis to TPE was 9 days • Range 0 – 91 days • 32/44 cases responded • Median time from diagnosis to TPE for responders vs. non-responders was 10 vs. 19 days (NS) Davenport R: J Clin Apher 2001

  41. Meta-Analysis Results Davenport R: J Clin Apher 2001

  42. Meta-Analysis Results Davenport R: J Clin Apher 2001

  43. Meta-Analysis Results • Biopsy with sclerosis or inadequate material • 3/26 responders vs. 9/10 non-responders (p<0.05) • Unable to evaluate effect of treatment regimen on outcomes (response or relapse) • 11 different treatment regimens used in 12 studies Davenport R: J Clin Apher 2001

  44. TPE for Recurrent FSGS – 2001 to 2006 • Four case series; 2 case reports (prolonged TPE) • 54 patients in case series • 42 children/ 12 adults • Remission achieved in 40-60% of patients

  45. TPE for Prevention of Recurrent FSGS • Ohta et al (Transplantation 2001) • Retrospective • Pediatric • Recurrence rates • 4/6 in non-PP group • 5/15 in PP group (2-3 TPE Rx) • High risk patient recurrence • Gohh et al (Am J Trans 2005) • Prospective • High risk patients • Previous allograft lost to recurrent FSGS • Rapid progression to ESRD (<3 years)

  46. Prospective TPE Prophylaxis for Recurrent FSGS Gohh RY et al: Am J Trans 2005

  47. TPE Prophylaxis for Recurrent FSGS Gohh RY et al: Am J Trans 2005

  48. TPE for ABO Incompatible Transplantation • Common for emergent hepatic transplantation • More common in Japan for LRD renal transplantation where DD kidney availability is poor • 10% of all DD transplants from 1989 to 2002 • UNOS data demonstrate O and B patients wait twice as long as A patients for a DD kidney • ABO antigens are located on the vascular endothelium of convoluted distal and collecting tubules

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