Indications for Plasmapheresis

1. Indications for Plasmapheresis Timothy E. BunchmanPediatric Nephrology & Transplantation

2. 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.

3. Goodpasture’s Syndrome • Anti-glomerular Basement Membrane Antibody Mediated Disease • Single CT (Johnson et al. Medicine 1985), case studies • TPE useful in rapid lowering of Anti-GBM Ab • Lower post-treatment serum creatinine, decreased incidence of ESRD • NEED ADJUNCT IMMUNOSUPPRESSIVE REGIMEN • Follow antibody levels for end point

4. Rapidly Progressive GN (non Anti-GBM) • RPGN- most patients have evidence of antibody associated disease (ANCA), or known immune complex disease - IgA, Cryoglobulinemia,lupus • Case reports (favorable), CT-no favorable generalized benefit (Cole et al. 1992, AJKD) (when TPE added to standard immunosuppressive therapy)

5. Rapidly Progressive GN (non Anti-GBM) • However: • Subset analysis revealed that TPE was beneficial for patients with severe disease or those requiring dialysis (Kaplan Ther Apheresis, 1997)

6. Multiple Myeloma with Renal Failure • Cast Nephropathy resulting from light chain toxicity • TPE in conjunction with proper anti neoplastic regimen improves on a more likely return of renal function • Evidence: CT (n=29) (Zucchelli et al. KI, 1988)- strong support • Recommend- 5 consecutive daily TPE treatments-early in course

7. Multiple Myeloma with Renal Failure • Caveats: • Must rule out other causes of renal failure as these patients tend to be relatively ill • If renal failure well established- results not as good- better before onset of oligoanuria (Johnson et al. Arch Intern med, 1990)

8. IgA Nephropathy & Henoch Schonlein Purpura • ~ 10% of IgA presents as RPGN • TPE rationale--removal of circulating IgA • Evidence No CTs, case reports Treatment +/- other immunosuppressive agents • Recommend: • Useful in RPGN presentation (Coppo et al. Plasma Ther Transfus Technol, 1985) • Likely minimal role in chronic disease

9. HSP(Hattori et al, Am J Kid Dis, 1999, 33:427-33) • 9 children with RPGN with HSP Rx with PP without immunosuppression • Proteinuria ~ 4.9 gms/m2 • GFR ~ 46 mls/min/1.73 m2 • 6/9 complete recovery • 2/9 rebound with proteinuria with progression to ESRD

10. Cryoglobulinemia • Renal Manifestations- glomerular capillary deposition of cryoglobulin or immune complex disease with complement activation and vasculitis • Evidence: No CTs, case reports and uncontrolled trials • Consensus: Useful adjunct in treatment of severe disease (progressive RF, coalescing purpura, advanced neuropathy) (D’Amico et al. KI, 1989)

11. Cryoglobulinemia • Caveat: • If Hep C associated disease interferon-alpha used as treatment (Misiani et al. NEJM, 1994) • Can use TPE as adjunct if disease reappears after discontinuing interferon in immediate period when considering reintroduction of interferon

12. Hemolytic Uremic Syndrome • Difficult at times to differentiate between TTP and HUS (TTP tends to have more neurological manifestations while renal failure predominates in HUS) • May be HUS associated with Shiga toxin, congenital (factor H deficiency) or caused by inciting drugs-cyclosporine, tacrolimus, quinine, Oral Contraceptives, or other diseases like SLE and carcinoma)

13. Hemolytic Uremic Syndrome • Evidence- limited-works in TTP? Why not HUS-adult outcome usually worse • SUBGROUPS: • Recurrent HUS in renal Transplantation- (Agarwal et al. JASN, 1995) Reviewed case reports- suggest TPE effective but endpoint unclear (ie continue until renal function returns) • HUS in Children- No RCTs, case reports suggest benefit of limiting renal damage in children with no diarrheal prodrome, neurologic manifestations or those >5 yrs of age (Gianviti et al. AJKD, 1993) • Recommend: Minimal data to support use except in subgroups above

14. Systemic Lupus Erythematosus • Evidence- early case reports suggested some benefit but CTs have not supported TPE when added to standard Immunosuppression (Lewis et al., NEJM, 1992) • May be some role in pregnancy when use of cytotoxic agents are not desired • ? Treatment refractory disease • Recommend: no evidence to support use

15. Antiphospholipid Antibody Syndrome, Anticardiolipin Antibodies, Lupus anticoagulant • Associated with venous & arterial thrombosis, fetal loss and occasional renal disease • Evidence- no CTs, case reports • Limited in renal disease- some benefit noted in patients treated for LA pregnancy associated thrombotic microangiopathy (Farrugia et al., AJKD 1992) • Recommend: May be useful when other interventions have failed

16. Scleroderma • Scleroderma with ANCA positive patients, normal renin levels, normotensive associated renal disease • Evidence: No CTs, case reports (2) • Seemed to offer clinical improvement (Omote et al., Inter Med, 1997) • Recommend: Consideration if poor disease control and patient ANCA positive

17. Focal Segmental Glomerulosclerosis • Group: Recurrence Post-transplant (15-55% recurrence)- thought to be due to a circulating factor not yet specifically isolated • Evidence - strong no CTs, case reports with clinical and proteinuria improvement (Artero et al., AJKD, 1994) • Recommend: Daily therapy (early) for up to 2 weeks

18. Focal Segmental Glomerulosclerosis • Group: Native FSGS • Multiple etiologies, therefore need to evaluate carefully • Evidence: equivocal- may offer benefit in treatment resistant forms of primary FSGS • Recommend: Clinically based

19. Panel Reactive Antibody Reduction • Transplant Candidates with high titers of cytotoxic antibodies- high rate of hyperacute rejection of transplanted grafts • Other therapies also offered-ie monthly IVIG infusions-currently undergoing trials • Evidence: used immunoadsorption column treatments- No CTs, some encouraging results in several case studies (Ross et al., Transplantation, 1993) • Recommend: High consideration in those unable to receive renal transplants due to elevated PRA

20. Acute Renal Vascular Rejection • Evidence: 2 controlled trials no significant benefit noted (Allen et al., Transplantation, 1983) • Recommend: No supportive evidence for TPE in this treatment

21. Acute Hepatic Failure(Singer et al, Ann Surg, 2001 234:418-24) • 49 children with FHF Rx with PP for • Hepatic support for recovery/bridge to Tx • Correction of coagulation • Results • 3/49 (8%) complete recovery • 32/49 (64%) bridge to Tx • 14/49 (28%) died due to FHF • No complications from PP

22. PP with or without HF in Sepsis • New generation of HF machines now have capability for PP • Can be done simultaneously with HF with all current machinery • Does data exist in this area?

23. (1.5 x HF BFR) (0.4 x citrate rate)

24. HF + Plasma filtration adsorption • 10 pts with SS • 10 hrs of PFA + CVVHD vs CVVHD alone • MAP > with PFA (p = 0.001) • 11.8 vs 5.5 mmHg • Norepi < with PFA (P =0.003 ) • 0.08 vs 0.005 • TNF alpha production > with PFA (p = 0.009) Ronco et al CCM 2002 30:1387-8

25. Plasma exchange and sepsis • 76 adult pts with DIC/MOSF/ARF-66% • Ventilated-72% • Shock-88% • Rx with PE until DIC reversed • Avg 2 (range 1-14) • Predicted mortality rate ~ 80% with Survival rate 82% (Stegmayr et al CCM 2003 31:1730-6)

26. Sepsis Rx with PE • Tetta C et al • Nephrol Dial Transpl 1998 13:1458-64 • Use of sorbent adsorption for cytokine removal • Nguyen el al Ped CCM 2001 2:187-196 • Rx with PE for Rx of microvascular thrombosis

27. Sepsis Rx with PE • Winchester et al Blood Purif 21:79-84 • Use of target sorbents • Tetta el al • Ther Apher 2002 :109-15 • Int Care Med 2003 29:1222-8 • Artif Organs 2003 27:202-13 • Sorbents, adsorption, PE

28. Indication of TPECategory 1: Standard acceptable therapy • Chronic idiopathic demyelinating polyneuropathy (CIDP), cryoglobulinemia, Goodpasture’s syndrome, Guillain-Barre syndrome, focal segmental glomerulonephritis, hyperviscosity, myasthenia gravis, post transfusion purpura, Refsum’s disease, TTP

29. Indication of TPECategory 2: Sufficient evidence to suggest efficacy usually as adjunctive therapy • ABO incompatible organ transplant, bullous pemphigoid, coagulation factor inhibitors, drug overdose and poisoning (protein bound), Eaton-Lambert syndrome, HUS, monoclonal gammopahty of undetermined significance with neuropathy, pediatric autoimmune neuropsychiatric disorder associated with streptococcus, RPGN, systemic vasculitis

30. Indication of 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.

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

32. Risk Benefit ratios • Difficulty of basing all decision on patient care on controlled trial data (retrospective or prospective) is that one will not advance thought process • If the therapy has known and controlled risks and is safe then do not the potential benefits potentially out weigh the risks?

33. Meta-analysis Meta-analysis

34. Acknowledgement • Thanks to Pat Brophy and Stuart Goldstein for many of these slides and thought processes