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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).
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.
INDICATIONS FOR PLASMA EXCHANGE
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
INDICATIONS FOR PLASMA EXCHANGE
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
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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%.
INDICATIONS FOR PLASMA EXCHANGE
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.
INDICATIONS FOR PLASMA EXCHANGE
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)
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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