Plasmapheresis

Dr.

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)

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

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Renal indications

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

 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

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Technical considerations
Today automated methods for cell separation

are available, These systems are essentially of two types: 1. Centrifugation 2. Plasma filtration

Technical considerations

 Technical

considerations

Technical considerations

Technical considerations

Technical considerations

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Dialysis & Transplantation 2009 February: 1-4

TA Technologies

Membrane

Centrifugation

Prisma Gambro BCT Asahi Plasma Flow Cascade apheresis for selective plasma component removal Specialized devices

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Apheresis in Clinical Practice

Sickle Cell Dis. Malaria

Thrombocytosis

RBC

WBC

PLT

Plasma

Leukemias Cell Therapies

TTP Guillain Barre Syn. Myasthenia Gravis Goodpastures Syn. Waldenstroms

Bloodletting and Plasmapheresis

When it comes to bloodletting three questions must be answered

Who?

When?
How much?

Which Replacement fluids

How much?
Volume of exchange

1-1.5 plasma volume

Calculation depends on numerous factors

Frequency of procedures Duration of therapy

Efficiency of Plasmapheresis
What is being removed?

Efficiency of Plasmapheresis
70 60 50 40 Percent 30 20 10 0

IgG - mainly extravascular IgM mainly intravascular

1 plasma vol 1.5 plasma vol 2 plasma vol

Exchange Fluids
5% Albumin

Best choice Dilute only with saline

Combination of saline and albumin

FFP
Cryopoor plasma

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.

Goodpastures 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

Rapidly Progressive GN (non AntiGBM)

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)

Rapidly Progressive GN (non AntiGBM)

However:

Subset analysis revealed that TPE was beneficial for patients with severe disease or those requiring dialysis (Kaplan Ther Apheresis, 1997)

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

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 treatmentsearly in course

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)

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

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

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) (DAmico et al. KI, 1989)

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

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 drugscyclosporine, tacrolimus, quinine, Oral Contraceptives, or other diseases like SLE and carcinoma)

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

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

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

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

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

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

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

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

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

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?

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

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

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)

Sepsis Rx with PE
Tetta C et al

Nephrol Dial Transpl 1998 13:1458-64 Use of sorbent adsorption for cytokine removal Rx with PE for Rx of microvascular thrombosis

Nguyen el al Ped CCM 2001 2:187-196

Sepsis Rx with PE
Winchester et al Blood Purif 21:79-84

Use of target sorbents

Ther Apher 2002 :109-15 Int Care Med 2003 29:1222-8 Artif Organs 2003 27:202-13

Tetta el al

Sorbents, adsorption, PE

Indication of TPE
Category 1: Standard acceptable therapy
Chronic idiopathic demyelinating polyneuropathy

(CIDP), cryoglobulinemia, Goodpastures syndrome, Guillain-Barre syndrome, focal segmental glomerulonephritis, hyperviscosity, myasthenia gravis, post transfusion purpura, Refsums disease, TTP

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), EatonLambert syndrome, HUS, monoclonal gammopahty of undetermined significance with neuropathy, pediatric autoimmune neuropsychiatric disorder associated with streptococcus, RPGN, systemic vasculitis

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.

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

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?

TTP A Thrombotic Microangiopathy

Microvascular Occlusive Disorder

Platelet thrombi
Thrombocytopenia Mechanical damage to erythrocytes 70% of patients are women

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
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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