Indications for Plasmapheresis

Timothy E. BunchmanPediatric Nephrology &

Transplantation

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.

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

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)

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)

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

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) (D’Amico 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 drugs-cyclosporine, 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)

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)

HF + Plasma filtration adsorption

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 Nguyen el al Ped CCM 2001 2:187-

196– Rx with PE for Rx of microvascular

thrombosis

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

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

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

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.

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?

Meta-analysis

Acknowledgement Thanks to Pat Brophy and Stuart

Goldstein for many of these slides and thought processes