new aphresis prof ehab wafa

PLASMAPHRESIS

By

Ehab M. Wahba Wafa,MD CONSULTANT OF

NEPHROLOGY&TRANSPLANTATION

Urology & Nephrology CenterMansoura University

Egypt

Plasma Exchange

Plasma exchange (PE) came into widespread clinical useafter early reports of beneficial effects in Goodpasture’sdisease in the mid-1970s.

It is used to remove many large-molecular-weightsubstances from plasma, including pathogenic antibodies,cryoglobulins, and lipoproteins.

Newer techniques allow more selective removal of plasmacomponents, such as double filtration plasmapheresis,cryofiltration, and immunoadsorption .

Apheresis in Clinical Practice

RBC PlasmaWBC PLT

Sickle Cell Dis.

Malaria

Leukemias

Cell Therapies

Thrombocytosis

TTP

Guillain Barre Syn.

Myasthenia Gravis

Goodpasture’s Syn.

Waldenstrom’s

TECHNIQUES

Centrifugal cell separators

hollow-fiber plasma filters and standardhemodialysis equipment( more commonly inrenal units)

Centrifugal devices:

Allow withdrawal of plasma with eithersynchronous or intermittent return of blood cells tothe patient.

No upper limit to the molecular weight of proteinsremoved

Blood flow rates are generally relatively low(90 to 150 ml/min).

Platelet counts can decrease by as much as 50%.

A centrifugal cell separator used for plasma exchange

Membrane plasma filtration:

Uses highly permeable hollow fibers with membrane poresof 0.2to 0.5 ìm.

All immunoglobulins will cross the membrane (IgG moreefficiently than IgM).

large immune complexes and cryoglobulinsmay not beadequately cleared.

Many membranes allow clearance of molecules up to 3million daltons.

There is no loss of platelets

Membrane plasma filtrationCont.

Hemolysis can occur if transmembrane pressuresare toohigh (a rare complication)

Blood flow rates required are 90 to 200 ml/min;

Membranes used in plasma filters are polysulfone,polypropylene,cellulose diacetate, polymethyl-methacrylate, or polyacrylonitrile.

The adsorptive properties of the membrane for cytokinesand other biomolecules may account for some of thebeneficial effects of plasma filtration.

Protein A immunoadsorption

Remove immunoglobulin alone from plasma, without the need for replacement fluids and without depletion of clotting factors and complement.

Protein A selectively binds the Fc domains of immunoglobulin Molecules.

The Immuno-adsorption columns can be repeatedly regenerated. Columns have been used for 1 year for a single patient on up to 30 occasions.

play a key pathogenic role in place of plasmaexchange in:

Goodpasture’s disease,

Rheumatoid arthritis, and systemic lupusvasculitis

Remove anti-ABO or anti-HLA antibodies inhighly sensitized transplant recipients.

Protein A immunoadsorption :cont

Protein A binds IgG

Double filtration plasmapheresis Cascade filtration)

Membrane filtration to separate cells fromplasma and then secondary plasma filtration(pore size, 0.01 to 0.03 ìm) to remove plasmasolutes based on molecular size.

Most albumin is returned to the patienttogether with lower molecular weightproteins

Mansoura Urology and Nephrology center

Double filtration

This waste will mainly contain largermolecules

immunoglobulins, immune complex, M-components and LDL-cholesterol

the need of plasma or albumin transfusion isgreatly reduced

Anticoagulation: heparin or nafamostatemesilate

Mansoura Urology and Nephrology center

Hemofenix Technology For Nanofilteration

Modern technologies allowproducing dialysismembranes with a porediameter of 20 nano-metres. One examples ofsuch a membrane is atrack-etched membrane,obtained from interactionbetween a polymer filmand ions accelerated in acharged particleaccelerator. Electron microphotograph of a track

membrane's surface (a) and chip (b).

/wiki/article1149

Hemofenix Nanofilteration

Blood plasma filtration(plasmapheresis) machineHemofenix-M, whose filteringelements are produced usingtrack membranes with pores up

to 100 nm in diameter.

J Nephrol Ther, vol4(4),2014 .

Hemofenix NanofilterationAdvantagesAllows performing the treatment with a single and

small needle and with reduced extra-coporealvolume(70 ml).

Low priming and short duration of treatment.

The exchange of low volumes allows not to useplasma as a replacement fluid so reduces the risk ofinfection and allergy as in PLE.

CAN BE COMPARABLE OR EVEN SUPERIOR Totraditional PLE AS IT IS MORE TOLERABLE AND LESSINVASIVE.

J Nephrol Ther, vol4(4),2014

INDICATIONS FOR PLASMAPHARESIS

Diseases Treated with TA

Guillain-Barre Syndrome 11%

Myasthenia Gravis 12%

CIDP 8%

Cryoglobulinemia 30%

Anti-GBM Disease 30%

Pauci-immune RPGN 13%

SLE nephropathy 10%

Myeloma kidney 7%

Recurrent FSG 5%

Renal transplantation 5%

INDICATIONS FOR PLASMA EXCHANGE

1-Anti–Glomerular Basement Membrane Antibody Disease(Goodpasture’s Disease)

Plasma exchange removes anti-GBM

Ab effectively ( after 7 to 10 plasma volume exchanges.

Antibody synthesis is inhibited by the concurrent use ofcyclo- phosphamide and corticosteroids.

70% to 90% of patients now survive.

PE with daily 4-liter exchanges should be initially for 14days

Pulmonary hemorrhage is an independent indication for PE.


2-Small-Vessel Vasculitis

Small-vessel vasculitis with severe renal failure (scr above5.5 mg/dl or dialysis dependent) or pulmonary hemorrhage.

3-Other Crescentic Glomerulonephritis

Post-infectious GN, GN associated with infectiveendocarditis, IgA nephropathy, membranoproliferativeglomerulonephritis (MPGN), and membranous nephropathy.

No good evidence for any benefit in RPGN not due to anti-GBM disease or vasculitis.

PE is reserved for IgA nephropathy , GN with rapidlydeteriorating renal function and extensive fresh crescents inthe biopsy specimen


4-Focal Segmental Glomerulosclerosis

PE and protein A immunoadsorption have beenused to treat patients with primary FSGS orrecurrent disease after transplantation.

PE is NOT recommend in primary FSGS.

No controlled trials of plasma treatments inrecurrent FSGS after transplantation


5- HUS/TTP

1- Diarrhea-Associated HUS

No study of plasma exchange in childhood HUS.

No controlled trials in adult D+ HUS, but uncontrolled

observations suggest possible benefit.

2-Thrombotic Thrombocytopenic Purpura

FFP and PE in TTP replenish vWF-cleaving protease(ADAMTS13) & to remove antibodies against it, and toremove the large vWF multimers from circulation.


3- Hemolytic-Uremic Syndrome

plasma exchange is used in all adults with TTP or D−HUS and perform all exchanges against FFP or cryo-poor FFP

Removal of auto-antibodies to vWF multimerscleaving enzyme and/or Infusion of vWF multimerscleaving enzyme.


6-SLE No benefit of plasma exchange over conventional

immunosuppression for renal, serologic, or clinicaloutcomes, in both the short and long term.

PE may benefit patients with : CrescenticGN, Pulmonaryhemorrhage.-Cerebral lupus.-Catastrophic antiphospholipidsyndrome-Lupus associated TTP.-Severe lupus unresponsiveto conventional drugs . Patients for whom cytotoxic therapyhas been withdrawn because of bone marrow suppressionor other toxicity.

Chan, T. M. Nat. Rev. Nephrol. 11, 46–61 (2015); published online 25

November 2014; doi:10.1038/nrneph.2014.215

A randomised controlled trial comparing the efficacy ofstandard of care (SOC) combined with plasma exchangeagainst SOC alone in patients with lupus nephritis revealed

no difference in terms of renal outcome. Beneficial effects have been reported in patients with

refractory disease course or in pregnancy with priorcomplications due to SLE and antiphospholipid syndrome.

Efficacy of plasma exchange and immunoadsorption in SLE and antiphospholipid syndrome

IAS seems to have beneficial effects in patients withrefractory disease, contraindications to standardimmunosuppression or during pregnancy.

The mechanism IAS relates to autoantibody removal but forplasma exchange removal of activated complementcomponents, coagulation factors, cytokines andmicroparticles

Autoimmunity Reviews 15 (2016) 38–49

Efficacy of plasma exchange and immunoadsorption in SLE and antiphospholipid syndrome

Both treatment forms have good safety profilesThere is a need to more clearly define the clinicalutility of plasma exchange and IAS in refractorylupus and APS subgroups.

There is a clear need to perform randomisedcontrolled trials to evaluate efficacy, safety andtolerability of both treatment strategies in thetreatment of SLE.


7-Cryoglobulinemia

a- Type I cryoglobulinemia

Usually associated with myeloma or lymphoma.

Monoclonal immunoglobulin causes hyperviscosity andcryo-precipitation.

Easily removed by plasma exchange, often with

immediate clinical benefit.


b- Type II (Mixed Essential) Cryoglobulinemia

Commonly in association with lymphoma and HCV.

Monoclonal antibody (usually IgM) with specificity for a second, usually polyclonal, immunoglobulin.

The resulting immune complexes can be deposited in the

microcirculation & particularly associated with MPGN.

PE is effective at clearing the immune complexes.

Arthralgia, skin lesions, and digital necrosis resolve with PE

Patients with RPGN can recover renal function.

Cytotoxic agents or rituximab prevent resynthesis of the cryoproteins

Long-term intermittent PE to control symptoms.

ANCA-Associated Glomerulonephritis

Results of clinical trial of apheresis therapies, eitherplasmapheresis or cytapheresis in AAV are disappointing.These studies showed no benefit. Benefits just in dialysisdependent patients or in preserving renal function..

In contrast to AAV, in anti-GBM RPGN, the beneficial effectof plasma exchange has been well established .It might beattributable to the direct role of anti-GBM antibody in thepathogenesis of anti-GBM antibody RPGN, while in AAV nodirect role for ANCA have been established

Contrib Nephrol. Basel, Karger, 2013, vol 181, pp 240–247

ANCA-Associated Glomerulonephritis

Japan nation wide survey of RPGN recommendscytapheresis in patients with aggressive forms ofRPGN (rapid deterioration of renal function) like thePR3-ANCA associated RPGN, or pulmonary renalsyndrome complicated by severe inflammation, or

relapses with high MPO-ANCA titer.

Yamagataet al.,Clinical Apheresis,20(4), 2005

Report from the European community group suggested

that adding plasma exchange to immunosuppressive

therapy was not beneficial if there was severe tubular

atrophy and fewer than 33 %of the glomeruli were normal

(De Lind van Wijngaarden et al., 1998)

Role of TPE IN ANCA-associated vasculitis


8-Myeloma

PE has benefit in myeloma with either cast nephropathy or light-chain renal toxicity .

PE should be reserved for patients with high light-

chain loads and cast nephropathy on biopsy.


9-Transplantation

a. Antibody-Mediated Rejection

PE combined with IVIG OR ATG, may effectivelyreverse such rejection episodes in 55%-100% ofepisodes.

No convincing evidence that PE has any role in the

treatment of chronic rejection.


9-Transplantation

B- Anti-HLA Antibodies

PE or immunoadsorption to reduce cytotoxic antibody levels Before transplantation to ensure a current negative CXM immediately before trans-plantation.

PE or immunoadsorption in addition to cyclo-phosphamide & pred. led to graft survival rates at 1 and 4 years of 77% and 64%.


9-Transplantation

C- ABO-Incompatible Renal Transplantation

Remove natural anti-A or anti-B bloodgroup antibodies from the recipient beforeliving related transplantation from an ABO-incompatible donor.


9-Transplantation

D-Recurrent FSGS

PE, double filtration PE, and proteinAimmunoadsorption have all been used to treatrecurrence of FSGS.

Intensive treatment regimens have led to morepersistent remissions.

All three apheresis modalities lower therecurrence

Myasthenia Gravis

Nerve

Anti-AchR Ab

Muscle

Acetylcholine (Ach)

AchR

Myasthenia Gravis

Plasmapheresis

Acute myasthenic crisis

Respiratory insufficiency

Failure to respond to medications

Side effects of medications (prednisone)

Before and after surgery (thymectomy)

Myasthenia Gravis

Before plasmapheresis After Plasmapheresis

Complications of Plasma Exchange

Hypotension, anaphylaxis,

citrate-induced paresthesia, urticaria ,hypocalcemia(presenting with perioral tingling and paresthesias)and citrate-induced metabolic alkalosis ( FFP ratherthan albumin).

Transmission of infectious diseases, especially viralsecondary to hypogammaglobulinemia .

Bleeding risk (FFP should be used if PT increased orfibrinogen decreased)

Dilutional hypokalemia

Red Cell Exchange

Sickle Cell Disease

Malaria

Babesiosis

Sickle Cell Disease

Clinical picture Chronic genetic anemia Hgb S instead of Hgb A alters the erythrocytes and their membranes

(sickle red cells) Increased blood viscosity Microvascular occlusion

Infarcts in brain, lungs, retina Pain crisis Priapism Acute chest syndrome Stroke

Treatment Red cell transfusionsHydroxyurea Red cell exchange (ASFA Category I)

Aims to maintain Hgb S <30

Malaria Cause

Plasmodium falciparum, vivax, ovale, malariae Transmitted by female anopheline mosqito Infected RBC adhere to endothelial cells of capillaries and

postcapillary venules via surface knobs Microvascular obstruction of brain, kidneys,lungs

Clinical picture Fever, malaise, headache Neurologic impairment Renal failure ARDS

Traetment Chloroquine, quinine, quinidine Red cell exchange (ASFA Category III) Plasmapheresis for removal of cytokines to prevent or treat lactic

acidosis, hypoglycemia (NR)

White Cell DepletionLeukapheresis

Leukocytosis Acute Myelogenous Leukemia (AML) Chronic Myelogenous Leukemia (CML) Acute Lymphocytic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL)

Clinical picture Hyperviscosity with microvascular occlusion

CNS symptoms Hemorrhage Pulmonary insufficiency

Treatment Combination chemotherapy (tumor cell lysis leads to metabolic

imbalance and ARDS) Leukapheresis (ASFA Category I)

Treatment of leukocytosis Prevention of tumor cell lysis syndrome

Plateletpheresis

Thrombocytosis (>1,000 x 10 /L) Essential Polycytemia vera

Clinical picture Microvascular occlusion

CNS symptomsHemorrhage Pulmonary insufficiency

Treatment Chemotherapy Plateletpheresis (ASFA Category I)

9

CONCLUSION I

Early introduction of plasma exchange appears tobe effective for various immunologic kidneydiseases.

However, plasma exchange primarily serves as anadjunct to other immunosuppressive therapies andis often expected to have beneficial role .

Early diagnosis and treatment of the underlyingcondition remains important.

CONCLUSION II

The strongest evidence for plasma exchange is forthrombotic microangiopathy, in which it serves asthe single most important therapy in most cases.

Further research is necessary to establish theoptimal dose and frequency of TPE and theappropriate replacement fluid and the plasmaproduct composition for each condition.

FUTURE DIRECTION

The new innovation of HemofenixNanofilteration using Track- EctedMembrane may solve the problemin selected & refractory cases andoffer superior outcome totraditional plasmaphresis

Th a n k Yo u

new aphresis prof ehab wafa

Healthcare