1. Plasmapheresis
Dr. Anand Banka
PGI

2. Introduction Plasma exchange
Has been used extensively for over four decades to treat a variety of renal diseases
Removal of large quantities of plasma (usually 2 to 5 L) from a patient and replacement by either fresh-frozen or stored plasma
The procedure is frequently referred to as “plasmapheresis” when a solution other than plasma (e.g. , isotonic saline) is used as replacement fluid
(“apheresis” from the Greek for “to remove” or “to take away”)

4. Introduction
Apheresis technology was Initially developed in the 1950s to harvest peripheral blood cells from healthy donors for transfusion into patients
Renal indications for therapeutic plasma exchange (TPE) continue to expand
Nephrologists are well trained to perform this extracorporeal blood purification treatment
Dialysis & Transplantation 2009 February: 1-4

5. Renal indications
Dialysis & Transplantation 2009 February: 1-4

6. J. Am. Soc. Nephrol. 1996; 7:367-86

7. Plasmapheresis
Method of treatment in which the plasma components separated with a plasma separator are subjected to plasma exchange (PE), plasma adsorption, double-filtration plasmapheresis with a secondary membrane, and other treatments
Dialysis & Transplantation 2009 February: 1-4

8. u55555555555555555555555ddddddddddddddddddd
Dialysis & Transplantation 2009 February: 1-4

9. Technical considerations
Today automated methods for cell separation are available,
These systems are essentially of two types:
1. Centrifugation
2. Plasma filtration

10. Technical considerations

11. Technical considerations

12. Technical considerations

13. Technical considerations

14. Technical considerations
Dialysis & Transplantation 2009 February: 1-4

15. Dialysis & Transplantation 2009 February: 1-4

16. TA Technologies Membrane Centrifugation Prisma Gambro BCT
Asahi Plasma Flow
Cascade apheresis for selective plasma component removal
Specialized devices

17. Dialysis & Transplantation 2009 February: 1-4

18. Apheresis in Clinical Practice
Sickle Cell Dis.
Malaria
Thrombocytosis
RBC
WBC
PLT
Plasma
Leukemias
Cell Therapies
TTP
Guillain Barre Syn.
Myasthenia Gravis
Goodpasture’s Syn.
Waldenstrom’s

19. Bloodletting and Plasmapheresis

20. “When it comes to bloodletting three questions must be answered”
Who?
When?
How much?
Which Replacement fluids

21. How much? Volume of exchange 1-1.5 plasma volume
Calculation depends on numerous factors
Frequency of procedures
Duration of therapy

22. Efficiency of Plasmapheresis
What is being removed?
IgG - mainly extravascular
IgM – mainly intravascular

23. Exchange Fluids 5% Albumin Combination of saline and albumin FFP
Best choice
Dilute only with saline
Combination of saline and albumin
FFP
Cryopoor plasma

24. 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.

25. 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

26. 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)

27. 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)

28. American Journal of Kidney Diseases, 2008: 52(6):1180-96

29. 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

30. 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)

31. 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

32. 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

33. 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)

34. 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

35. 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)

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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?

46. (1.5 x HF BFR)
(0.4 x citrate rate)

47. 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 :1387-8

48. 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 :1730-6)

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

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

51. Indication of TPE Category 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

52. Indication of TPE Category 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

53. Indication of TPE Category 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.

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

55. 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?

56. TTP – A Thrombotic Microangiopathy
Microvascular Occlusive Disorder
Platelet thrombi
Thrombocytopenia
Mechanical damage to erythrocytes
70% of patients are women

59. TPE with Dialysis Equipment
When therapeutic plasma exchange is performed with a highly permeable filter and standard dialysis equipment, it is often referred to as membrane plasma separation (MPS)
Having undergone considerable investigation and use in both Europe and Japan, MPS has become increasingly popular in the United State
Dialysis & Transplantation 2009 February: 1-4

60. Conclusions
Nephrologists and their dialysis staff are well trained to manage the TPE procedure
An analysis of the prevailing charges and reimbursements would suggest that providing TPE with dialysis equipment would increase the availability and decrease the cost of this highly effective and potentially lifesaving procedure

61. Thank You!