plasmapheresis WHY WHEN AND HOW

DR AYMAN SEDDIK, M.sc, MD
ASS.PROF.NEPHROLOGIST AIN SHAMS UNIVERSITY
NEPHROLOGY CONSULTANT
DUBAI HEALTH AUTHORITY
DR AYMAN SEDDIK , PLASMAPHERESIS WHY ,
WHEN AND HOW

Outline
Introduction to aphaeresis
therapies
Why ….. Plasmaphaeresis
hypothesis
When ……. Therapeutic indications
How …… technical aspects
WHEN AND HOW

History
 The term plasmapheresis is derived
partly from the Greek word apheresis,
which means “taking away” or removal.
It is unclear when the notion of
therapeutic removal of blood
components first originated, but it was
flourishing even before Hippocrates in
the fifth century bc .
 Bloodletting to remove evil “humors”
was a commonplace medical practice,
partly because of the lack of
understanding of disease processes and
the paucity of effective therapies
WHEN AND HOW

WHEN AND HOW

Effectivenessof TPE dependson:
 Volume of plasmaremoved relative to total plasma
volume
 Distribution of substance to be removed
 Between intra and extravascular compartments
 Speed at which the substance equilibrates between
compartments
 Rate at which substance is synthesized

Normal Immunoglobulins
One plasma volume exchange:
 IgG drops to 34% of baseline
 IgA drops to 39% of baseline
 IgM drops to 31% of baseline
 Varying reports as to time to recovery of Ig
 Ranges from 3 days to 5 weeks to full recovery
 Variation due to different methods of calculating
recovery, some patients on immunosuppressive
medications

Metabolic Characteristics of Plasma Proteins
Protein Concentration
in plasma
(mg/mL)
% intravascular Change in
catabolism with
decrease conc.
Molecular
weight
(kDa)
IgG 12.1 45 Decrease 150
IgA 2.6 42 Constant 160
IgM 0.9 76 Constant 950
IgD 02.6.02 75 Increase 175
IgE 0.0001 41 Increase 190
Albumin 42 40 Decrease 66
Fibrinogen 2-4 80 Constant 340
C3 1.5 53 240
A2
macroglobulin
100 constant 820

Spectrum of Blood Purification
 Bun 28,Urea 60
 Vitamin B12 1,355
 Vancomycin 1,468
 2-microglobulin11.600
 Albumin 69,000
 IgG 180,000
 IgM 900,000
 LDL-cholesterol 1,300,000
 Cell
HD HF
Plasma
exchange
Double filtration
plasmapheresis
Cytapheresis

MECHANISMS OF DOUBLE FILTRATION
PLASMAPHERESIS
Plasma
Plasma separator
Blood
cells
Plasma filter
IgG, Immune complex,
Lipoprotein, etc.

PLASMA LEVELS OF IGG BEFORE AND AFTER
PLASMAPHERESIS

Complications
WHEN AND HOW

HOW ?
WHEN AND HOW

Advantages Disadvantages
Membrane
apheresis
Fast and efficient
plasmapheresis
No citrate requirements
Can be adapted for
cascade filtration
Removal of substances limited by
sieving coefficient of membrane
Unable to perform cytapheresis
Requires high blood flows, central
venous access
Requires heparin anticoagulation,
limiting use in bleeding disorders
Centrifugal
devices
Capable of performing
cytapheresis
No heparin requirement
More efficient removal
of all plasma components
Expensive
Requires citrate anticoagulation
Loss of platelets
Brenner: Brenner and Rector's The Kidney, 8th ed 96

Portion of Plasma
Volumea
Exchanged (Ve/Vp)
Volume
Exchanged
(Ve, mL)
Immunoglobulin or
Other Substance
Removed (MRR, %)
0.5 1,400 39
1.0 2,800 63
1.5 4,200 78
2.0 5,600 86
2.5 7,000 92
3.0 8,400 95
aPlasma volume = 2,800 mL in a 70-kg patient, assuming
hematocrit = 45%.
Ve, volume of plasma exchanged; Vp, estimated plasma
volume; MRR, macromolecule reduction ratio.
Handbook of Dialysis 97

Why
 Pathologic Factors Removed by Plasmapheresis
 Autoantibodies
Immunecomplexes
Myeloma proteins
Cryoglobulin
Complement products
ADAMTS13 (metalloproteinase)
Lipoproteins
Protein-bound toxins
 ADAMTS13,A memberof the ADAMTS (A Disintegrin And Metalloproteinasewith
Thrombospondin Motifs) family of peptidases.
WHEN AND HOW

When
plasmapheresis in renal diseases
 Summary of Renal Diseases Treated with
Plasmapheresis
 DISEASE CATEGORY :
 Antiglomerular basement membrane disease I
 Rapidly progressive glomerulonephritis II
 Hemolytic uremic syndrome III
 Thrombotic thrombocytopenia purpura I
 Renal transplant rejection IV Desensitization for renal transplantation II
 Recurrent focal segmental glomerulosclerosis III
 Cryoglobulinemia II
 Systemic lupus erythematosus III
∗ Category I, Standard primary therapy; category II, supportive therapy; category III,
when the evidence of benefit is unclear; category IV, when there is no current
evidence of benefit or for research protocols.
WHEN AND HOW

A) Use of
Plasmapheresis in
Renal Disease
WHEN AND HOW

1-Anti–glomerular Basement
Membrane Disease:
 Anti–glomerular basement membrane (anti-GBM) disease
is a disorder in which circulating antibodies are directed
against the noncollagenous (NC1) domain of the α3 chain
of type IV collagen, which results in rapidly progressive
glomerulonephritis (RPGN). Goodpasture’s syndrome is
classically defined as the triad of pulmonary hemorrhage,
RPGN, and circulating anti-GBM antibodies. More than
90% of affected patients have circulating anti-GBM
antibodies, the titer of which is correlated with disease
activity. 6 7 Approximately 60% to 70% of patients have
pulmonary disease in addition to RPGN, and in rare cases, a
patient has pulmonary hemorrhage and no renal
involvement
WHEN AND HOW

ANTI-GBM ANTIBODY
 Goodpasturesyndrome
(lung and kidney
involvement)
 Anti-GBM disease (only
kidney involvement)
 Note: 10-40%of patients
may be ANCA positive.

Anti–Glomerular Basement Membrane Disease:
 Before the use of current therapies, the mortality rate
exceeded 90%, and the mean survival time after diagnosis
was less than 4 months. Currently, with the combination of
plasmapheresis, corticosteroids, and cyclophosphamide,
the mortality rate has been reduced to less than 20%. The
role of plasmapheresis in anti-GBM diseases is the rapid
removal of the pathogenic antibodies; cyclophosphamide
and the corticosteroids are essential to prevent additional
antibody synthesis and to reduce inflammation. A rapid
reduction in anti-GBM antibody levels is necessary in view
of the speed of glomerular damage, and this cannot be
achieved by drug therapy alone.
WHEN AND HOW

Anti–glomerular Basement
Membrane Disease:
 Plasmapheresis was first used for the treatment of
anti-GBM disease in 1975, 8 and numerous
uncontrolled studies and series publishedsince the
mid-1980s have suggested the beneficialeffectof
plasmapheresis on overall survival and renal
preservation rates. Some of the major studies 9 10 11 12 13 14
15 are summarized in Table 67-3 , and although none
were prospectiverandomized trials, the use of
plasmapheresis is now considered standard therapy.
WHEN AND HOW

KIDNEY TRANSPLANT AND
RECURRENCE POST ANTI GBM
DISEASE
 Most patients with anti-GBM disease who undergo
kidney transplantation have no recurrence of the
disease in the allograft, although up to 50% may show
linear immunoglobulin G (IgG) staining of the
glomerularbasement membrane. 18 The delayof
kidney transplantation for 12 months after the
disappearanceof anti-GBM antibodiesand the degree
of immunosuppression necessary to maintain a
functioning renal allograft are thought to be the main
reasons why recurrences are very rare.
WHEN AND HOW

2-rapidly Progressive Glomerulonephritis
 RPGN is characterized by rapid deterioration in renal function occurring over a
period ranging from a few days to a few weeks. Untreated RPGN usuallyleads
to end-stage renal disease. RPGN is characterized by severeinflammation and
necrosisof most glomeruli and, frequently, by fibrocellularcrescents
(crescenticglomerulonephritis). Thereare three major subgroups of RPGN: (1)
anti-GBM diseaseand Goodpasture’s syndrome(discussed previously); (2)
immunecomplex–mediated processesin which immune deposition occurs,
usuallyas a resultof autoimmunediseasessuchas systemiclupus
erythematosus, postinfectious processes, mixed cryoglobulinemia,and
immunoglobulin A nephropathy; and (3) pauci-immunediseases thatare most
often (in about 80% of patients) associatedwith anti–neutrophil cytoplasmic
antibody (ANCA), including necrotizing granulomatous vasculitis(formerly
known as Wegener’s granulomatosis),or microscopic polyarteritis. A
therapeutic role for plasmapheresis in anti-GBM diseaseis discussed previously
in this chapter, and its role in immunecomplex mediated processes is still
uncertain (see later discussion).
WHEN AND HOW

Crescentic Glomerulonephritis
 I: Anti-GBM type
(3%)
 II: Immune-
complex type (45%)
 III: Pauci-immune
type(50%)

 For pauci-immune ANCA-associated diseases
(necrotizing granulomatous vasculitis and microscopic
polyarteritis), plasmapheresis was used initially because
the renal pathologic processes of these disorders were
similar to those of Goodpasture disease; in fact, some
patients have both anti-GBM antibodies and ANCA.
Plasmapheresis was first used for the treatment of RPGN
associated with necrotizing granulomatous vasculitis in
1977; the combination of plasmapheresis, oral
prednisolone, and cyclophosphamide was associated with
rapid renal recovery
WHEN AND HOW

PAUCI-IMMUNE
 Wegener’sgranulomatosis (WG)
 Microscopic polyangiitis(MPA)
 Renal-limited necrotizing crescentic
glomerulonephritis(NCGN)
 Churg-Strauss syndrome
 Note: 80-90% of patients are ANCA positive.

 However, several studies through the 1990s did not demonstrate
an additional benefit for the use of plasmapheresis in the
treatment of ANCA-associated diseases. For example, the
Hammersmith Hospital reported a controlled trial of
plasmapheresis in focal necrotizing glomerulonephritis with 48
patients randomly assigned to receive conventional treatment
with oral steroids and cyclophosphamide, followed by
azathioprine, with or without intensive plasmapheresis (at least
five exchanges in the first 7 days). There was no benefit for
patients with moderate or severe renal disease who were not
dialysis dependent at presentation. 21 However, the results of this
study were the first to suggest that some patients who were
dialysis dependent might be able to discontinue dialysis after
treatments that included plasmapheresis (10 of 17 patients
receiving plasmapheresis versus 3 of 8 patients not receiving
plasmapheresis).
WHEN AND HOW

 The Canadian ApheresisStudy Group randomlyassigned32 patients
with RPGN toreceive intravenousmethylprednisolone, followedby
oral prednisoloneand azathioprine, withorwithoutplasmapheresis(10
exchanges in thefirst 16 days). Again, no benefitof plasmapheresiswas
demonstratedin the non–dialysis-dependentpatients; however, a
nonsignificanttrend in benefitwas observed in thedialysis-dependent
patients: of four patientsreceiving plasmapheresis, threewere ableto
discontinuedialysis, in comparison with onlytwo of seven control
subjects. 22 In 62 patientswith Churg-Strausssyndromeor polyarteritis
nodosa, patientswhoreceived plasmapheresis in addition to
cyclophosphamideand steroidsexhibitedno additional benefit. 23
More recently, in a prospective, multicenterstudy, Zaunerand
associates24 randomlyassigned39 patientswith RPGN toreceive
immunosuppressivetherapyaloneor immunosuppressivetherapyand
plasmapheresis; theyfound thatplasmapheresis had no significant
effect on renal or patientsurvival, independentlyof age, sex, or serum
creatininelevel at thetimeof diagnosis
WHEN AND HOW

 However, other studies have shown that plasmapheresis treatmentmay
improve prognosis in patients with ANCA-associated glomerulonephritis.
Frasca and colleagues 25 restrospectivelyanalyzeddatafrom 26 patients with
acute renal failure caused by ANCA-associated vasculitis. Theyreported that
the patients who received immunosuppressivetreatmentplus plasmapheresis
experienceda more favorable outcome than did patients who received
immunosuppressivetreatmentalone. Results from the multicenterEuropean
Vasculitis Study Group have also been reported. 26 27 In this randomized,
controlled clinical trial, plasmaexchange wascompared with intravenous
methylprednisolone in ANCA-associated vasculitis in patients with severe
renal involvement(creatinine level >500 μmol/L, or >5.7 mg/dL). All patients
receivedoral cyclophosphamide for 3 months, followed by azathioprine.
Treatmentwith plasmapheresis wasassociatedwith lower incidenceof dialysis
dependenceat 12 months; these results, together with those of previous
studies, provide strong support for additional therapywith plasmapheresis in
patients with severeANCA-associated glomerulonephritis and advanced renal
failure
WHEN AND HOW

 However, other studies have shown that
plasmapheresis treatment may improve prognosis in
patients with ANCA-associated glomerulonephritis.
Frasca and colleagues 25 restrospectively analyzed data
from 26 patients with acute renal failure caused by
ANCA-associated vasculitis. They reported that the
patients who received immunosuppressivetreatment
plus plasmapheresis experienced a more favorable
outcome than did patients who received
immunosuppressivetreatment alone. Results from the
multicenter European Vasculitis Study Group have also
been reported
WHEN AND HOW

 In conclusion, data now support plasmapheresis as having
a beneficial role in the treatment of patients with ANCA-
associated vasculitis and severe kidney failure at
presentation. In patients with ANCA and anti-GBM
disease, as well as in any patient with diffuse pulmonary
alveolar hemorrhage, plasmapheresis is beneficial for the
recovery and reduction of risk progression to dialysis. 30 31 32
Therefore, plasmapheresis is, at present, the best
complement to immunosuppressive therapy for patients
with advanced kidney disease from these mechanisms of
injury. The usefulness of plasmapheresis for less severe
kidney disease, however, remains unresolved.
WHEN AND HOW

 Finally, there is little evidence for the use of
plasmapheresis in other causes of RPGN, although
there is one report of benefit in children with RPGN
from Henoch-Schönlein purpura. 34 Results of one
study 35 suggest that plasmapheresis may be beneficial
in kidney transplant recipients with recurrent
Henoch-Schönlein purpura nephritis, but no
prospectivestudies or protocols have yielded results
indicating the optimal therapeutic regimen in this
group of patients.
WHEN AND HOW

RANDOMIZEDTRIAL OF PLASMA EXCHANGE OR HIGH-DOSAGE
METHYLPREDNISOLONEAS ADJUNCTIVE THERAPY FOR SEVERE RENAL
VASCULITIS
David R.W. Jayne. J Am Soc Nephrol 18: 2180–2188, 2007
MEPEX

3-Lupus Nephritis
 Acute and chronic kidney diseases are common and
potentially serious complications of systemic lupus
erythematosus. Traditionally, lupus nephritis was treated
with corticosteroids, azathioprine, and intravenous
cyclophosphamide, but safer and more effective therapies
have been sought. More recent studies have shown that
mycophenolate mofetil 36 is an alternative to intravenous
cyclophosphamide in patients with active proliferative
disease; rituximab 37 has also been considered as alternative
in the treatment of proliferative lupus nephritis, but data
suggest that rituximab is not effective in the treatment of
refractory disease
WHEN AND HOW

 The use of plasmapheresis for patients with
proliferative lupus nephritis was first reported in the
1970s, but it was not until the Lupus Nephritis
CollaborativeStudy Group in 1992 undertook a
randomized study to systematicallyexamine the safety
and efficacy of plasmapheresis. The Lupus Nephritis
CollaborativeStudy Group 38 was a large, randomized,
controlled multicenter trial comparing a standard-
therapy regimen of prednisone and cyclophosphamide
with a regimen of standard therapy plus
plasmapheresis in patients with severe lupus nephritis.
WHEN AND HOW

 Forty-six patients were randomly assigned to receive
standard therapy, and 40 were randomly assigned to
receive plasmapheresis. Histologiccategories included
lupus nephritis types III, IV, and V. Plasmapheresis was
carried out three times per week for 4 weeks, and drug
therapy was standardized. The mean follow-upperiod
was 136 weeks. Although patients treated with
plasmapheresis experienced more rapid reduction of
antibodies to double-stranded DNA and
cryoglobulins,the addition of plasmapheresis did not
improve clinical outcomes
WHEN AND HOW

 Of the 46 patients who received standard therapy, 8 (17%)
developed kidney failure and 6 (13%) died; in comparison, of the
40 patients who received plasmapheresis, 10 (25%) developed
kidney failure and 8 (20%) died. Results were similar in
magnitude and direction after an extended follow-up of 277
weeks. Another small trial confirmed these findings: Wallace
and colleagues 39 randomly assigned nine patients to receive
either 6 months of intravenous cyclophosphamide and
prednisone and nine to receive plasmapheresis before each
infusion of cyclophosphamide. In each group, two patients
developed end-stage renal disease, and three patients achieved
renal remission at 24 months. Together, the results of these
studies show that addition of plasmapheresis to conventional
treatment for lupus nephritis does not improve the prognosis of
lupus nephritis, despite more rapid reduction in circulating
autoantibodies
WHEN AND HOW

 The main side effects were herpes zoster, and four women
developed irreversible amenorrhea. Danieli and associates 41
compared two groups of patients with proliferative lupus
nephritis at 4 years of follow-up. The first group (12 patients)
received synchronized therapy with plasmapheresis and
cyclophosphamide, whereas the second group (16 patients)
received intermittent cycles of cyclophosphamide; at the end of
the follow-up period, the patients who received synchronized
therapy achieved remission faster than did the other group, but
their renal outcomes were not superior at long-term follow-up
analysis. Yamaji and colleagues 42 reported a retrospective
analysis of 38 patients in which they found that synchronized
therapy with plasmapheresis and cyclophosphamide might be
superior to plasmapheresis or cyclophosphamide alone in
achieving complete remission of lupus nephritis and in
minimizing the risk of relapse.
WHEN AND HOW

 Thus, the availablepublishedevidence does not
support the addition of plasmapheresis to
immunosuppressivetherapy for lupus nephritis. As a
result, the American Society for Apheresis considered
plasmapheresis as a category IV (no evidence) therapy
for lupus. 43 Although plasmapheresis does not
demonstrate clear benefits in severe lupus nephritis,
immunoadsorptionwith protein A, protein C1q, or
dextran sulfate cellulosecolumns was shown in small
case series to be useful in treating refractory lupus
nephritis
WHEN AND HOW

3-Mixed Cryoglobulinemia
 Cryoglobulinemia is the presence of serum proteins that
precipitate at temperatures below 37°C and redissolve on
rewarming. More than 80% of patients with mixed
cryoglobulinemia (in which the cryoglobulin contains both a
polyclonal IgG [which may either act as an antigen or be directed
against an antigen] and a monoclonal IgM rheumatoid factor
directed against the IgG) are infected by hepatitis C virus, and
cryoglobulinemia can often be found in patients with
membranoproliferative glomerulonephritis related to this virus.
The glomerular injury is the consequence of glomerular
deposition of immune complexes, and the renal manifestations
range from isolated proteinuria to overt nephritic or nephrotic
syndrome, with variable progression toward end-stage renal
disease.
WHEN AND HOW

 The use of plasmapheresis for cryoglobulinemia has not been studied in
randomized,controlled trials; however, the notion that plasmapheresis may
removepathogenic cryoglobulins is rational, and numerous anecdotalcase
reports and uncontrolled studies have demonstrated that plasmapheresis may
benefit patients with severeactive diseasemanifested by progressive kidney
failure, severeor malignant hypertension, purpura, and advancedneuropathy.
46 47 In the treatmentof severeacute flaresof cryoglobulinemia with
glomerulonephritis or vasculitis,one approach is combination antiviral therapy
with peginterferon and ribavirin for 48 weeks, plus corticosteroidsand
cyclophosphamide as needed to control severesymptoms. In the most severe
cases, the addition of plasmapheresis (exchangesof 3 L of plasma three to four
times per week for 2 to 3 weeks)can be helpful. In uncontrolled studieswith
more than five patients, plasmapheresis induced rapid reduction in the
cryocrit, improved kidney function in 55% to 87% of patients, and improved
survival (≈25% mortality rate) in comparison to historical data (≈55% mortality
rate). 48
WHEN AND HOW

 Becauseof the unique characteristics of cryoglobulins,
the plasmapheresis technique has been modified to
enhance their removal. Cryofiltration cools the plasma
in an extracorporeal circuit, allowing for more efficient
removal of the pathogenic proteins. However, this
technique is most efficientlyperformed by a
continuous process that requires a specialized
machine designed for this purpose.An alternative
protocol is a two-step procedure in which the patient’s
own plasmacan be reinfused after incubation in the
cold to cause the abnormal proteins to precipitate out.
49
WHEN AND HOW

4-kidney Failure Associated With Multiple Myeloma
And Other Hematologic Disorders
 Renal disease is a common finding in multiple myeloma; in
20% to 50% of affected patients, the plasma creatinine
concentration exceeds 1.5 mg/dL (133 μmol/L). Kidney
function can be impaired by a variety of factors, including
precipitation of myeloma light chains within renal tubules
(Bence-Jones proteins) that can lead to direct tubular
toxicity. Other factors frequently implicated in myeloma
associated kidney failure include hypercalcemia,
hyperuricemia, amyloidosis, hyperviscosity, infections, and
chemotherapeutic agents. 50 Plasmapheresis could be of
benefit in preventing tubular damage by the removal of
nephrotoxic Bence-Jones proteins.
WHEN AND HOW

Paraproteins
 Removal of paraproteins (ie myeloma) is 50% of
predicted
 Some cases can have greater removal than predicted (see
last 2 reasons)
 Due to:
 Increase in plasma volume (up to 1.5x greater, especially
if IgG >40g/L)
 Some myeloma patients have higher proportion of IgG
in intravascular space (56-85%)
 As remove paraprotein in TPE, plasma volume
progressively decreases

 An earlystudy of 29 patients with multiple myelomaand acute kidney injury
included 24 patients on dialysis andan additional 5 with creatinine
concentrations higher than 5 mg/dL. The patients were randomlyassigned to
one of two groups: 15 patients received plasmapheresis plus standard therapy,
and 14 patients received standard therapyalone. Of the 15 patients who
received plasmapheresis, 13 patients recovered renal function (creatinine
concentration < 2.5 mg/dL), in contrast to only 2 of the 14 receiving standard
therapy. 51 However, in a study of 21 patients who were randomlyassigned to
receiveeither plasmapheresis pluschemotherapyor chemotherapyalone,
Johnson and colleagues 52 reported no difference in patient survivalor in
recoveryof kidney function. The mortality rate at 6 months was 20% in each
group, which increased to 60% to 80% at 12 months. In the largeststudy to
date, 97 patients with multiple myelomaand acute kidney injury were
randomlyassigned to receiveeither conventional therapyalone or conventional
therapy plus five to seven plasma exchanges (5% human serum albumin) of 50
mL per kilogramof body weightfor 10 days. Theprimary endpoint (death,
dialysis,or glomerularfiltration rate <30 mL/min) occurred in 33 (56.9%) of 58
patients who received plasmapheresis and in 27 (69.2%) of 39 control subjects.
53
WHEN AND HOW

 Together, the results of these studies leave unresolved
the role of plasmapheresis in the management of cast
nephropathy. Questions remain about subgroupsof
patients who may benefit; in general, these results
suggest that caution be used when plasmapheresis is
considered for patients with acute kidney injury in
association with multiplemyeloma.
WHEN AND HOW

 Waldenström’s macroglobulinemia is a B cell disorder resulting
from the accumulation of clonally related immunoglobulin M
(IgM)–secreting lymphoplasmacytic cells. The morbidity
associated with Waldenström’s macroglobulinemia is typically
mediated by tissue infiltration by neoplastic cells and by the
physicochemical and immunologic properties of the monoclonal
IgM. In affected patients with symptomatic hyperviscosity,
cryoglobulinemia, or moderate to severe cytopenia, the burden
of plasma paraproteins should be reduced rapidly. In these
circumstances, plasmapheresis can be initially performed.
Typically, two to three sessions of plasmapheresis are necessary
to reduce serum IgM levels by 30% to 60%. Treatment should be
initiated as soon as possible with a regimen that includes
bortezomib, dexamethasone, and rituximab to achieve more
rapid disease control.
WHEN AND HOW

 Plasmapheresis has been widely used in hematologic and
oncologic diseases; however, only the following disorders
are considered category I (standard primary therapy) by
the American Society for Apheresis: (1) leukocytosis and
thrombocytosis (cytapheresis), (2) thrombotic
thrombocytopenic purpura (TTP; discussed next section),
(3) posttransfusion purpura (plasmapheresis), (4) sickle
cell disease (red blood cell exchange), (5) ABO-
incompatible bone marrow transplantation (red blood cell
removal from the marrow, plasmapheresis in the recipient
to eliminate ABO antibodies is considered category II
[supportive therapy]), (6) hyperviscosity in monoclonal
gammopathies, and (7) cutaneous T cell lymphoma
(photopheresis).
WHEN AND HOW

5-Thrombotic Thrombocytopenic Purpura
and Hemolytic Uremic Syndrome
 TTP and hemolyticuremic syndrome(HUS) sharea spectrum of
abnormalitiesin numerousorgan systemsand arecharacterized by the
presence of thrombocytopeniaand microangiopathichemolytic
anemia.
 In HUS, the prominentfeatures are hemolyticanemia,
thrombocytopenia,and advanced acute or chronickidneydisease. The
finding of neurologicsymptomswith fever and perhaps lesssevere
kidney failure is classicallyconsidered TTP.
 However, these designationsareartificial,and both syndromesare
characterizedwith pathologicchanges of endothelialinjury and
plateletmicrothrombi. With twoexceptions, thecauses for these
disordersremain unknown and can be viewed as complicationsof drug
therapy(mitomycin, cyclosporine, ticlopidine), autoimmunedisorders
(systemiclupus erythematosus, anti–phospholipidantibody
syndrome), and pregnancy.
WHEN AND HOW

Sadler J E Blood 2008;112:11-18
©2008 by American Society of Hematology
pathogenesis
 TTP has been shown to be
associated with a severe (<5%)
deficiency of plasma ADAMTS13

 One well-defined cause of HUS is the syndrome associated
with hemorrhagic diarrhea caused by Escherichiacoli
O157:H7. In this disease, the enterotoxin induces colonic
vascular injury, which leads to systemic absorption and
activation of numerous pathways and results in endothelial
cell damage over several days. Platelet microthrombi are
particularly prominent in the glomerular capillaries and
often cause severe renal failure. Thedisease is often self-
limited in children, and a role for plasmapheresis is not
clear. In adults and in patients with severe or persistent
disease, plasmapheresis is often used. In the largest
uncontrolled trial for plasmapheresis in E. coli –associated
HUS, 22 patients in Scotland were confirmed to have E. coli
O157:H7 infection.
WHEN AND HOW

 Plasmapheresis could be performed in only 16
patients, of whom 5 (31%) died; of 6 patients who did
not receive plasmapheresis, 5 (83%) died of the
disease. There is also evidence from a single report
about 60 patients that plasmapheresis improves
outcomes with ticlopidine-associated HUS-TTP
(mortality rates, 50% of control subjects vs. 24% of
plasmapheresis recipients 59 ). However, there is no
evidence for a beneficialrole of plasmapheresis in
patients with HUS-TTP secondary to cancer
chemotherapy, calcineurin inhibitors, or bone marrow
transplantation.
WHEN AND HOW

 The mechanism of some causes of TTP are now
partiallyunderstood and reveal why plasmapheresis
with plasmaexchange is beneficial. Genetic studies of
congenital TTP led to the identification of defects in
the metalloproteinase named von Willebrandfactor
(vWF)–cleavingprotease (A Disintegrin-like And
Metalloprotease with Thrombospondin type 1 repeats
[ADAMTS13]).
WHEN AND HOW

 TTP can result from the accumulation of ultra-large
vWF. Multimers of VWf normally accumulate on the
endothelial cell membrane and are rapidlycleaved into
normal-sized multimers by the ADAMTS13protease.
In some patients, ADAMTS13deficiency leads to
accumulation of ultra-large VWf multimers, resulting
in platelet microthrombus formation and subsequent
microangiopathic hemolytic anemia. An inhibitory
autoantibodyto the ADAMTS13 metalloproteinase has
been found at varying titers among a high percentage
of patients with the idiopathicform of this disease
WHEN AND HOW

 By removing autoantibodies to ADAMTS13and
replacing with normal plasma (containing ADAMTS13
activity), plasmapheresis can reverse the TTP
syndrome caused by ADAMTS13deficiency. However,
ADAMTS13deficiency may be necessary but is not
sufficient to account for many cases of TTP.
Furthermore, enzyme activity is significantlyreduced
in numerous other conditions, including infection,
cancer, cirrhosis, uremia, systemic lupus
erythematosus, and disseminated intravascular
coagulation.
WHEN AND HOW

 Before theintroductionof plasma infusion and plasmapheresis,the
disease rapidlyprogressedand was almost uniformlyfatal (90%
mortalityrate). 64 In 1977 it was discovered that infusion of fresh-frozen
plasma orplasmapheresiswith fresh-frozen plasmareplacement could
reverse thecourse of disease. 65 66 Theefficacy of plasmaexchange in
thetreatmentof TTP-HUS in adultswas demonstratedin two trials
that included 210 patients.67 68 Plasmaexchangewith fresh-frozen
plasma was moreeffective than plasma infusion alone. At 6 months,
theremission ratewas 78% versus 31%, respectively,and thesurvival
rates with thesetwo procedures were 78% versus 50%, respectively.
Patientstreatedwithplasmaexchange received approximatelythree
times as much plasma as those treatedwith plasmainfusion alone
(wherebytheamount of plasma administrationwaslimitedby therisk
of volume overload). Therefore,it is possiblethat the benefitobserved
with plasmaexchange may have resultedfrom infusion of more plasma
ratherthan from theremoval of a toxicsubstance.
WHEN AND HOW

 Theoptimal duration of plasmapheresis treatmentfor HUS-TTP is not
known, but it is performed dailyuntil theplateletcount has risen to
nearlynormal and evidence for hemolysis(schistocytes,elevationof
lactosedehydrogenaselevels) has resolved. 60 A wide rangeof
exchanges (3 to 145) have been reported; on average, 7 to 16 daily
exchanges are necessary to induce remission. 60 64 67 68 The American
Associationof Blood Banks recommends daily plasmapheresisuntil the
plateletcount exceeds 150,000/μLfor 2 to 3 days, and the American
Societyfor Apheresisrecommends daily plasmapheresisuntil the
plateletcount is above 100,000/μLand lactosedehydrogenaselevel is
nearlynormal. 69 When present, neurologicsymptomsrapidly improve,
and theserum lactosedehydrogenaselevel tendsto improveover the
first 1 to 3 days. Theplateletcount may not rise for several days, and
improvementsin renal function often take longer. Patientsrequiring
dialysisat presentationmay be able to recoverenough function to
discontinuedialysis, but manypatientshave residual chronickidney
disease.
WHEN AND HOW

 When a normal plateletcount has been achieved,
plasmaexchange is graduallytapered by increasing the
interval between treatments. Many patients (one third
to one half) abruptlydevelop recurrent
thrombocytopenia and increased evidence of
hemolysiswhen daily plasmaexchanges are tapered or
stopped. Some of these patients may benefit from the
addition of prednisone or other immunosuppressive
therapy (cyclosporine, rituximab), although few data
validateany benefitsof these agents.
WHEN AND HOW

6-Recurrent Focal Segmental
Glomerulosclerosis
 Focal segmental glomerulosclerosis (FSGS) is a
common cause of end-stage renal failure, and
recurrent primary FSGS occurs at a rate of 20% to 30%
in kidney transplant recipients. The risk of relapse is
particularlyhigh (80% to 90%) in such patients with a
prior history of allograft loss resulting from recurrent
FSGS. Additional factors associated with an increased
risk of recurrence are rapid progression to end-stage
renal disease, mesangial hypercellularity, and younger
age
WHEN AND HOW

 The mechanisms of recurrent FSGS and early
detection of proteinuria after kidney transplantation is
unclear, but the earlyreappearance of proteinuria
suggests that a circulating factor that alters glomerular
permeabilityand cannot be eliminated bydialysis may
be present
WHEN AND HOW

 Removal of a circulating factor by immunoadsorption
or plasmaexchange may account for the remission of
the disease in some patients. 72 The potential
circulating factor may be a nonimmunoglobulin
protein with a molecularweightof less than 100 kDa,
although there are discrepancies on the characteristics
of this permeabilityfactor
WHEN AND HOW

 An alternative hypothesis is that nephrotic patients
lack one or more factors necessary for the
maintenance of normal glomerularpermeability,and a
factor in normal serum (i.e., clusterin) may be lost or
diminished. 73 74 75 However, at this time the
mechanisms of recurrent proteinuria and FSGS remain
unresolved.
WHEN AND HOW

 The treatments currently available for recurrent FSGS are
immunosuppressive drugs (cyclophosphamide and
methylprednisolone), plasmapheresis, and, according to some
reports, rituximab. Zimmerman 76 first reported on a 38-year-old
patient with recurrent FSGS who was successfully treated with
plasmapheresis. Cochat and colleagues 77 studied three patients
with recurrent FSGS in a prospective uncontrolled trial in which
early plasmapheresis was used in combination with
methylprednisolone pulses and cyclophosphamide over a 2-
month period. All three patients achieved remission within 12 to
24 days, which suggests that plasma exchange instituted early in
the course of recurrent nephrotic syndrome may be beneficial in
patients with FSGS. Artero and associates 78 treated nine patients
within 1 week of the onset of proteinuria; seven had a mean
reduction in protein excretion from 11.5 to 0.8 g/day, and these
remissions were sustained for up to 27 months.
WHEN AND HOW

 In recurrent FSGS after kidney transplantation,
beneficial results have been reported in children
treated with plasmapheresis and cyclophosphamide.
In a study of 11 children with recurrent FSGS after
transplantation, nine were treated with
plasmapheresis (6 to 10 times over 15 to 24 days), and
in seven, remission persisted after a follow-upof 32
months. 79 Likewise, in Cheong and colleagues’ 80
report of six children with recurrent FSGS, treatment
with plasmapheresis plus cyclophosphamide resulted
in complete or partial remissions in all the patients
WHEN AND HOW

 With regard to adult patients, controlled trials are lacking, but
early plasmapheresis is also recommended. Deegens and
associates 81 analyzed data from 23 patients with FSGS and renal
transplants, of whom 13 were treated with plasmapheresis and 10
were historical controls. After a median follow-up of 3.5 years, 2
(15%) patients who had been treated with plasmapheresis had
lost their allografts, in comparison with all 10 controls. In the
patients with recurrent proteinuria, FSGS recurred within 4
weeks after transplantation (77%), and plasmapheresis was
initiated within 14 days of recurrence (85%). In most studies,
researchers reported a remission rate between 70% and 80%, but
33% of patients experienced relapse after the end of the
treatment. 82 Nevertheless, retrospective evaluation of patients
managed without plasmapheresis indicates that early rates of
graft failure were as high as 80%; therefore, plasmapheresis is
indicated as initial therapy for recurrent FSGS.
WHEN AND HOW

 Some reportshave suggested thatfor individualsat high risk,
preemptivetreatmentwith plasmapheresisin the pretransplantationor
perioperativeperiod may alteror even prevent disease recurrence. In
Ohta and associates’ 83 report, 15 patientsreceived preoperative
plasmapheresis, and FSGS recurred in 5 (33%), whereas of 6 who did
not receive preoperativeplasmapheresis, 4 (66%)developed
recurrence. Gohh and colleagues 84 reportedon 10 patientsat high risk
for FSGS recurrence because of rapid progressiontorenal failure ( n =
4) or priorposttransplantationrecurrence of FSGS ( n = 6). Patients
underwent a course of eightplasmapheresistreatmentsin the
perioperativeperiod. Seven patients, including all 4 with first grafts
and 3 of 6 with priorrecurrence, were free of recurrence at follow-up
(238 to 1258 days), and the final serum creatinineconcentrationin 8
patientswith functioningkidneys averaged 1.53 mg/dL. Therefore, the
use of preoperativeand prophylacticpostoperativeplasmapheresis
appears promising in patientsat high risk, but controlledmulticenter
trialsarewarrantedto delineatetheoptimal preventiveapproach.
WHEN AND HOW

7-Kidney Transplantation
 Plasmapheresis has been used in different clinical
scenarios involving kidney transplantation. These
include ABO blood group–incompatibletransplants,
positiveT cell cross-match, acute humoral rejection,
and FSGS in the transplant
WHEN AND HOW

ABO-Incompatible Kidney
Transplantation
 The ABO blood group antigen system was discovered on
red blood cells by K. Landsteiner in 1901; these antigens are
expressed throughout the body, and in the kidney they are
found in the distal tubules, collecting tubules, and vascular
endothelium of peritubular and glomerular capillaries.
 The ABO antibodies (isoagglutinins) are produced in the
first years of life by sensitization to environmental
substances such as food, bacteria, and viruses and are
usually of the IgM type.
 These antibodies against ABO antigens generally preclude
kidney transplantation across ABO barriers and are the key
mediators of antibody-mediated rejection.
WHEN AND HOW

 In the earlydays of kidney transplantation, the results
with ABO-incompatibleorgans were disappointing. In
1981, Slapak and colleagues 89 described a patient with
blood group O who inadvertently received a
mismatched kidney from a donor of bloodgroup A; 2
days after transplantation, the patient experienced
acute rejection that was treated successfullywith
plasmapheresis.
WHEN AND HOW

 Twenty months after transplantation, the patient had
normal kidney function. From 1982 to 1989, Squifflet
and associates 90 performed 39 ABO-incompatible
kidney transplantations and were the first group to
attempt kidney transplantation with ABO
incompatibilities. The protocol to prepare the living
donor recipient included two to five plasmapheresis
sessions, pretransplantation immunosuppressive
therapy, and splenectomy to remove antibodies; graft
survival rates were better among the patients younger
than 15 years (89% at 5 years) than among those older
than 15 years (77% at 5 years).
WHEN AND HOW

 In Japan, ABO-incompatiblerenal transplantationflourished in the
1990s, and theoutcomes to date have been excellent. Takahashi and
colleagues 91 reportedtheoutcomes of 441 ABO-incompatiblekidney
transplantationsperformed at 55 centersacross Japan from 1989 to
2001. Therates of graft survival were 84% in the first year and 59% at 9
years of follow-up; theserates of survival were not statistically
significantin comparison with historicrecipientsof ABO-compatible
living donororgans. Thetherapyused to prepare therecipients
consistedof four components: (1) extracorporeal immunomodulation
to removeAB antibodiesbefore thetransplantation, (2) use of
immunosuppressivedrugs, (3) splenectomy, and (4) anticoagulation
therapy. Plasmapheresisand immunoadsorptionwerethetwo
techniquesperformed to remove theAB antibodies,and thegoal with
eithertechniquewas to decrease pretransplantationserum AB titersby
8- to 16-fold. Antibodyremoval was usuallynot performed after
transplantation.
WHEN AND HOW

 The Japanese literature has emphasized the need for
splenectomy at the time of transplantation, but the Johns
Hopkins group has established a preconditioning protocol
of plasmapheresis, cytomegalovirus hyperimmune globulin
(CMVIg), and anti-CD20 (rituximab) to enable the success
of ABO-incompatible renal transplantation without
splenectomy. The treatment protocol requires four to five
preoperative sessions of plasmapheresis to remove anti-A
and anti-B antibodies, and each session is followed by the
administration of CMVIg. After achieving
pretransplantation A- and B-antibody titers of less than 1:16
WHEN AND HOW

 a singledose of rituximab is given 1 or 2 days before
transplantation. Thereafter, immunosuppression
therapy with tacrolimus and mycophenolate mofetil is
initiated, followed by steroids and daclizumabafter
transplantation. Postoperative treatment included
another three sessions of plasmapheresis and CMVIg
administration on days 1, 3, and 5. The 5-yeargraft
survival rate for a cohort of 60 consecutive patients
was of 88.7%.
WHEN AND HOW

 Plasmapheresis has been used with
methylprednisolone for the treatment of acute
antibody-mediatedrejection in patients with ABO-
incompatiblerenal transplants. In five patients with
acute antibody-mediatedrejection after they received
ABO-incompatiblekidney transplants, Gloorand
colleagues 94 95 treated with plasmapheresis and
steroids, and three patients demonstrated
improvements in renal function
WHEN AND HOW

Positive T Cell Cross-Match
 High sensitization to HLA indicates positiveT cell
cross-matches with multiplepotential donors. The
degree of sensitization is quantified as the percentage
of the donor pool with which the serum of the patient
had positiveT cell cross-matches: the panel reactive
antibodystatus. The patients whosepanel reactive
antibodiesare persistently higher than 50% are
generallyconsidered “highlysensitized”
WHEN AND HOW

Kidney International(2011) 79, 583 – 586.

Therapeutic strategies antibody-
mediated rejection

 primary sensitization results from exposure to foreign HLA
antigens through transplantation, transfusion, or
pregnancy, although infection and other conditions can
also alter sensitization status. Patients with preformed
antibodies against HLA antigens have a lower probability of
receiving a matched kidney from a deceased or living
donor. Furthermore, presensitized recipients experience
less favorable outcomes after deceased-donor kidney
transplantation and are at increased risk for hyperacute or
acute antibody-mediated rejection and graft loss.
Successful transplantation in these patients requires a
protocol of desensitization to a specific donor in order to
reduce the risk of hyperacute rejection and immediate graft
loss
WHEN AND HOW

 The general approach in protocols to reduce HLA
antibodies involves the use of high-dose IgG and
plasmapheresis. Plasmapheresis is performed to remove
anti-HLA antibodies and is followed by infusion of low
doses of IgG during hemodialysis. The rationale is that low-
dose IgG has beneficial immunomodulating effects.
Concurrently with plasmapheresis initiation, patients are
treated with tacrolimus, mycophenolate mofetil, steroids,
and antimicrobial prophylaxis. Plasmapheresis is
continued thrice weekly until the T cell cross-match is
negative, and transplantation usually takes place within 24
hours. Plasmapheresis and low-dose IgG are usually
repeated several times during the first 2 weeks after
transplantation to remove any rebounding antibody.
WHEN AND HOW

 Plasmapheresis-based protocolsare usually not
suitable for highlysensitized patients awaiting
deceased-donortransplantation becausethe
availabilityof suitableorgans is unpredictableand
plasmapheresis is both difficultand very expensiveto
continue indefinitely; if plasmapheresis is stopped,
anti-HLA antibodytiters rebound
WHEN AND HOW

Acute Humoral Rejection
 Acute humoral rejection is characterized by severe allograft
dysfunction in association with the presence of circulating
donor-specific antibodies. Very poor outcomes are
observed with acute humoral rejection, and treatment with
pulse steroids and antilymphocyte therapy is often
ineffective. 100
 Removal of the donor-specific antibodies with
plasmapheresis has been successful when this treatment is
combined with tacrolimus and mofetil mycophenolate. 101 It
is now proposed that the combination of plasmapheresis
and IVIG may lead to short-term recovery from acute
antibody-mediated rejection in more than 80% of cases
WHEN AND HOW

b)Use of
Plasmapheresis in
NONRenal Disease
WHEN AND HOW

Plasmapheresis and Nonrenal
Disease
 According to several national registries, TTP, myasthenia gravis,
chronic inflammatory demyelinating polyneuropathy,
Waldenström’s macroglobulinemia, and Guillain-Barré
syndrome are the most frequent indications for plasmapheresis,
and results of randomized controlled trials have been indicative
of benefits for patients with these disorders. 104 There are now
nearly 100 rational indications for plasmapheresis, and the
American Society for Apheresis published an exhaustive review
of the experimental data supporting the different indications for
plasmapheresis. 56 In many clinical settings, the nephrologist is
asked to initiate plasmapheresis. Therefore, it is essential that
nephrologists be generally familiar with the literature supporting
the use of plasmapheresis for these conditions.
WHEN AND HOW

 Plasma exchange is a well-establishedtherapeutic
procedure commonly used in many neurologic
disorders of autoimmune origin. It is thought that the
beneficialeffects of plasmapheresis occur through the
removal of inflammatory mediators, including
autoantibodies,complement components, and
cytokines. Guillain-Barré syndrome, myasthenia
gravis, chronic inflammatory demyelinating
polyneuropathy,and demyelinating polyneuropathy
with IgG/immunoglobulinA are considered category I
indications by the American Society for Apheresis
WHEN AND HOW

Guillain-Barré syndrome
 Guillain-Barré syndrome develops shortly after an
infection, most commonly caused by Campylobacter jejuni.
A large number of diverse antibodies against different
glycolipids, including GM1, GD1a, and GQ1b, have been
describedPlasma Exchange in Guillain-Barré Syndrome 108
established the optimal numbers of plasmapheresis
sessions in the treatment of this disease: two for patients
with mild disability and four for patients with moderate
and severe disability. Plasmapheresis is considered as
efficacious as IVIG therapy, and combined treatment of
plasmapheresis and IVIG does not seem to yield additional
benefit.
WHEN AND HOW

Chronic inflammatory
demyelinating polyneuropathy
(CIDP)
 is a common and potentially treatable diseasewith an
estimated prevalence of about 1 to 2 per 100,000 adults.
Symmetric weakness in both proximal and distal
muscles that progressively increases for more than 2
months is the pivotal symptom in the diagnosis of this
disease. CIDP is associated with impaired sensation,
absence or diminishment of tendon reflexes, an
elevated protein level in cerebrospinal fluid,
demyelinating nerve findings in conduction studies,
and signs of demyelination in nerve biopsyspecimens.
WHEN AND HOW

 The presence of autoantibodiesagainst various
proteins and glycolipidsof the peripheral nerve in
samplesof serum and cerebrospinal fluid from
patients with CIDP may provide a rationale for the
therapeutic use of plasmapheresis. The treatments
most widelyused for CIDP consist of IVIG,
plasmapheresis,and corticosteroids. According to
publisheddata, there appears to be no difference in
efficacyamong these three main therapies
WHEN AND HOW

Myasthenia gravis
 is an autoimmune-mediated disorder of the neuromuscular
junction, clinically characterized by fluctuating muscle
weakness and fatigability. The most common variant of the
disease is mediated by circulating autoantibodies against
the nicotinic acetylcholine receptor (AChR). Mechanisms
responsible for loss of functional nicotinic AChR that
compromise neuromuscular transmission include the
degradation of the receptor, complement-mediated lysis of
the receptor, and interference with neurotransmitter
binding. In subgroups of patients negative for nicotinic
AChR antibody, antibodies against the receptor tyrosine
kinase can be detected.
WHEN AND HOW

 Thetreatmentof myastheniagravisincludes thymectomy,
acetylcholineesteraseinhibitors, corticosteroids, immunosuppressive
agents, plasmapheresis, and IVIG. It is presumed that byeliminating
circulating nicotinicAChR antibodiesandother humoral factors,
plasmapheresisaccounts for theobserved beneficial effects.
Indicationsfor plasmapheresisinclude situationsthat necessitaterapid
clinical improvement, such as myastheniccrisis, impending crisis, and
preoperativestabilization; patientsin whom long-termcontrolof
symptomsis suboptimal with otherforms of therapyalso benefitfrom
plasmapheresis. On occasion, patientsrequirelong-termoutpatient
exchange in order to achieveadequatecontrol of myastheniagravis
symptoms. Treatmentconsistsof four to sixexchanges, each removing
3 to 5 L of plasma, performed dailyor every otherday. Theduration of
maximal improvement is 2 to 3 weeks in 65% of cases, and anydegree
of improvementlasts less than 3 monthsin 68% of cases. Sometimes
patientshave a more prolongedresponse.
WHEN AND HOW

Catastrophic antiphospholipid
syndrome (CAPS)
 is a rapidlyprogressive and life-threatening disease
that results in thromboses in multipleorgans in the
presence of antiphospholipid antibodies. Rapid-onset
thromboses in multipleorgans and extensive
involvement of small and medium-sizedvessels in
atypical locations are the general characteristics of
CAPS
WHEN AND HOW

 Treatment with anticoagulation, corticosteroids, and
plasmapheresis or IVIG can be initiated. Plasmapheresis
can remove pathologic antiphospholipid antibodies, as well
as cytokines, tumor necrosis factor-α, and complement
products. Although plasmapheresis improves outcomes in
patients with CAPS, most reports of such patients have
specified plasmapheresis with fresh-frozen plasma as the
replacement fluid. Fresh-frozen plasma contains natural
anticoagulants (such as antithrombin III and protein C), as
well as clotting factors, so it is unknown whether
plasmapheresis per se or the fresh-frozen plasma
replacement provides the benefits to patients with CAPS.
No randomized controlled studies of plasmapheresis use in
this condition are currently under way.
WHEN AND HOW

familial hypercholesterolemia
 the successful use of plasmapheresis was first described in
1975. Subsequent reports showed that long-term, repetitive
procedures had a beneficial effect on aortic and coronary
atherosclerosis and significantly prolonged survival in
comparison with untreated siblings with homozygous
familial hypercholesterolemia. However, although
plasmapheresis is still used in some centers to treat severe
hypercholesterolemia, low-density lipoprotein (LDL)
apheresis is now accepted as the treatment of choice for
patients with homozygous familial hypercholesterolemia
and for heterozygotes with cardiovascular disease
refractory to lipid-lowering drug therapy.
WHEN AND HOW

REMOVAL OF TOXINS
 Plasmapheresis has also been used to remove toxins, depending
on the effective clearance, plasma protein binding, and volume
of distribution of the toxic substance. Plasmapheresis is used to
treat mushroom intoxication by Amanita phalloides, but some
reports suggest that forced diuresis is the treatment of choice. 120
There is controversy about the beneficial effect of
plasmapheresis in the treatment of life-threatening intoxications
with tricyclic antidepressants, benzodiazepines, quinine, and
phenytoin. Other drugs such as L-thyroxine, verapamil,
diltiazem, carbamazepine, and theophylline, as well as heavy
metals, are removed effectively by plasmapheresis, but the
overall change in total body toxin level is usually not clinically
significant. Because of the lack of controlled studies, it is
difficult to make recommendations for the treatment of
poisonings and overdoses
WHEN AND HOW

Pregnancy and Plasmapheresis
 Plasmapheresis can be performed safely during pregnancy,
and introduction of plasmapheresis during pregnancy for
diseases necessitating that procedure has improved
maternal and fetal survival rates.
 Plasmapheresis has been safely carried out in patients with
myasthenic crisis, Guillain-Barré syndrome, anti-GBM
disease, acute fatty liver of pregnancy, and TTP. Until the
effectiveness of plasmapheresis was recognized, the rate of
mortality from TTP was 95%; in cases of pregnancy-related
TTP, maternal survival was rare, and the fetal mortality rate
approached 80%. Since 1990, numerous reports have
revealed the efficacy of plasma exchange, and TTP has
become a curable disease, with a response rate of about
80%, with minimal or no sequelae
WHEN AND HOW

RISK
 Plasmapheresis can result in premature delivery
because hormones crucial in maintaining pregnancy
are removed. Other complicationscan result from
hypovolemic reaction, allergy, transitory cardiac
arrhythmias, nausea, and impaired vision. During the
exchanges, hypotension must be carefully monitored
and corrected, and in the second or third trimester, it
is preferable to place the patient on her left side to
avoid compression of the inferiorvena cava by the
gravid uterus
WHEN AND HOW

 For most conditions, the aim of this procedure is the
removal of pathologic autoantibodiesor toxins, and
the initial treatment goal is to exchange 1 to 1.5 times
the plasmavolume per plasmapheresis procedure. This
lowers plasma macromolecule levels by 60% to 75%,
respectively.
WHEN AND HOW

 Estimated plasma volume(in liters)=
0.07×weight(in
kg)×(1−hematocrit)
WHEN AND HOW

 For removal of components restricted predominantly to the
plasma space, the use of higher exchange volumes requires
significantly longer procedure times and yields no
additional clinical benefit. The ultimate clinical success of
the procedure depends on both the abundance of the
abnormal protein in plasma and its rate of production.
Unless the removal of the protein by plasmapheresis is
combined with additional therapies (usually
immunosuppressive or cytotoxic) to eliminate or reduce
the source of the abnormal protein or proteins, the
procedure is unlikely to provide clinical benefit. The time
needed to suppress abnormal protein production can be
several weeks; that is why plasmapheresis protocols often
require daily apheresis (or near daily) for prolonged times.
WHEN AND HOW

COMLICATIONS
Complications involving vascularaccess
 Hematomas
 Pneumothorax
 Catheter infections
Complications involving replacementfluids
 Anaphylactoid reactions to fresh-frozen plasma
 Coagulopathies
 Transmissionof viral infections
 Hypocalcemia
 Hypokalemia
Other complications
 Hypotension
 Dyspnea
 Thrombocytopenia
 Removalof erythropoietin and drugs bound to plasma proteins
WHEN AND HOW

REGISTERY PROVED COMPLICATIONS
 The Swedish Therapeutic Apheresis Registry reported
on more than 14,000 procedures from 1996 to 1999;
adverseevents occurred in 4.2% of procedures; no
fatalitieswere reported; and 1% of all the apheresis
procedures had to be interrupted becauseof an
adverseevent. The most common adverseeffects
reported were paresthesias (0.52%), hypotension
(0.5%), urticaria (0.34%), shivering, and nausea. This
events were most frequent in patients with
Goodpasture’ssyndrome (12.5%), patients with
TTP/HUS (10.5%), and patients with Guillain-Barré
syndrome (11.0%).
WHEN AND HOW

 In another report of 17,940 procedures performed on 3583
patients, 144 adverse events occurred in 3.9% of all
procedures. The following adverse reactions were
documented: reactions related to citrate toxicity (3%),
vasovagal reactions and hypotension (0.5%), vascular
access–related complications (0.15%), reactions related to
fresh-frozen plasma (0.12%), hepatitis B from fresh-frozen
plasma (0.06%), arrhythmias (0.01%), hemolysis caused by
inappropriate dilution of 25% albumin (0.01%), and one
death (from underlying disease) during a plasmapheresis
procedure (0.006%). No significant bleeding complications
were observed. Patients receiving fresh-frozen plasma had
significantly higher rates of adverse reactions than did
patients receiving other exchange fluids.
WHEN AND HOW

HYPOCALCEMIA
 One of the most frequent complications of plasmapheresis is hypocalcemia,
related to citrate infusion as anticoagulantfor the extracorporeal system orto
the fresh-frozen plasmaadministeredasa replacementfluid. 145 Citrate binds to
free calcium to form solublecalcium citrate, thereby lowering the free (but not
the total) serum calcium concentration. Hypocalcemia is manifested by
perioral and distal extremity paresthesias. Symptoms can be prevented and
reduced by administrationof either intravenous or oral calcium if the
plasmapheresis session lasts longer than an hour. Either the administrationof
oral calcium carbonate or the addition of calcium gluconate to the return fluid
is a useful maneuverto prevent hypocalcemia. 146 Theincidenceof
hypocalcemicsymptoms is loweredwith the prophylactic administrationof
calcium; in one study, without calcium prophylaxis, the incidenceof symptoms
was 9.1% (six in 66 treatments), whereas withcalcium prophylaxis, the
incidencewas reduced to 1% (six in 633 treatments). Marquesand Huang 147
reported an incidenceof hypocalcemiaof 3% when calcium gluconate is
infused in 5% albumin.
WHEN AND HOW

Electrolytes
 Potassium decrease (minimal)(0.25meq/L with
albumin and up to 0.7meq/L with FFP
 No change in sodium and glucose
 Bicarbonatedecrease 6meq/L and chloride increase
4meq/L with albuminand this reverses with FFP
(more citrate in FFP)

METABOLIC ALKALOSIS
 Another complication of citrate administration is the
development of metabolic alkalosis, but critical levels of
bicarbonate higher than 35 mEq are rarely seen. Risk
factors are use of fresh-frozen plasma and the presence of
concurrent renal failure (i.e., TTP), because the excess of
citrate generates bicarbonate, the excretion of which is
limited by the renal failure. Replacement regimens
involving saline and albumin solutions can result in a 25%
reduction in the plasma potassium concentration in the
postapheresis period, and this can be minimized by adding
4 mEq of potassium per liter to the replacement solution.
Hypokalemia is also a consequence of metabolic alkalosis.
WHEN AND HOW

HYPOTENSION
 Plasmapheresis can lead to a reduction in blood pressure,
usually as a result of a decrease in intravascular volume.
Because the volume of extracorporeal whole blood is
greater with intermittent centrifugation techniques,
hypotension episodes are more common than with
continuous modalities. Hypotension can also occur in
response to complement-mediated reactions to the
membrane filter or as a sensitivity to the ethylene oxide
that is used to sterilize the membrane. Fresh-frozen plasma
is also associated with anaphylactoid reactions that, in rare
cases, result in death. Reactions to fresh-frozen plasma are
most often characterized by fever, rigors, urticaria,
wheezing, and hypotension.
WHEN AND HOW

PULMONAARY EDEMA
 The developmentof dyspneasuggests that pulmonary
edema is present as a result of fluid overload;
noncardiogenic edema can occur in rare instances as a
component of anaphylactic reactions. Another cause
of acute-onset dyspnea is the presence of massive
pulmonaryemboli that have been reported to develop
when the reinfused blood components are not
adequately anticoagulated
WHEN AND HOW

COAGULOPATHY
 Plasma exchange with albumin replacement produces a
predictable decrease in clotting factors that may predispose
to bleeding ( Table 67-5 ). A single plasma volume
exchange increases the prothrombin time by 30% and the
partial thromboplastin by 100%; these changes revert
toward normal within several hours, but with repeated
plasmapheresis sessions, these abnormalities can persist.
In reported studies, the most significant change is in the
fibrinogen levels. Keller and associates 148 reported that
fibrinogen levels were lowered to 25% of levels before
apheresis and recovered to baseline levels after 2 to 3 days.
Therefore, 3 to 4 units of fresh-frozen plasma should be
substituted as the replacement fluid each week or sooner in
patients at risk for bleeding
WHEN AND HOW

Coagulant Proteins
Fibrinogen:
 Decrease to 25% of pretreatment with single exchange
of 1 PV
 Decrease to 10-30% of pretreatment with consecutive
daily 1 PV exchange
 recover to 100% of pretreatment levels by 2-3 days

Coagulant Proteins
Prothrombin:
 Decreased to 30% of baseline
Factor VII & factor VIII:
 Decreased to 45-50% of baseline
Factor IX:
 Decreased to 60% of baseline
Factor V, X, XI:
 Decrease to 38% of baseline
Antithrombin:
 Activity to 40%, Ag to 70%

Thrombocytopenia
 Thrombocytopenia is also a consequence of plasma
removal; removal of larger volumes is associated with
greater platelet loss, and the mean reduction in
platelets after a plasmapheresis procedure ranges from
9.4% to 52.6%. Clinical bleeding associated with
plasmapheresis is rarely reported, and when
plasmapheresis-related hemorrhage is present, it is
more likelyto bea consequence of thrombocytopenia
or inadequate heparin neutralization
WHEN AND HOW

IMMUNEDEFICIENCY STATE
 Removal of immunoglobulinsand complementcould
result in an immunodeficientstate. However, in a
randomized, controlled trial of plasmapheresis in
patients with lupus nephritis, TTP, or multiple
myeloma, patients receiving plasmapheresis were not
more prone to infection than were the other patients.
151 Nevertheless, repeated apheresis treatments with
albumin replacement deplete the patient’s reserve of
immunoglobulinsfor several weeks. If an infection
occurs, a single infusion of IVIG (400 mg/kg) restores
the plasma immunoglobulinconcentration toward
normal.
WHEN AND HOW

BLOOD TRANSMITTED DISEASES
Although estimates for the risk of viral
transmission by the use of fresh-frozen
plasma are low, the large volumes from
multiple donors increase the risk in
patients receiving long-term
plasmapheresis therapy. Use of large-
volume plasma units collected from a
single donor and the use of hepatitis B
vaccine may reduce the risk of virally
transmitted infections.
WHEN AND HOW

DRUG REMOVAL
 Substantial drug removal by plasmapheresis occurs with
drugs that are highly protein bound and therefore
primarily limited to the vascular space. Of the drugs used
to treat renal diseases, prednisone is not substantially
removed, whereas cyclophosphamide and
azathioprineare removed to some extent. This
potential problem can be circumvented by administering
the drug after a plasma exchange treatment
 ALWAYS GIVE YOUR PULSE CYCLOPHOSPHAMIDE
POST PLASMAPHERESIS SESSION NOT BEFORE
WHEN AND HOW

Drug Removal
 Can remove:
 ASA, tobramycin, dilantin,vancomycin, propranolol
 May reduce plasma levels of enzymes that metabolize
drugs
 May reduce plasma levels of proteins that bind and
transport drugs
 Depends on distribution of drug between
intra/extravascular space, half life of drug in circulation,
timing of administration of drug, protein bound status, not
lipid or tissue bound
 1% of prednisone removed
 IVIG mainly removed as remains intravascularly
 Ideally give medications after exchange

ACE INHIBITORS
 Flushing, hypotension, abdominal cramping, and other
gastrointestinal symptoms have been reported during
plasmapheresis in patients receiving angiotensin converting
enzyme (ACE) inhibitors. In one report of 299 consecutive
patients undergoing plasmapheresis, these atypical symptoms
occurred in all 14 patients who received an ACE inhibitor, in
contrast to only 7% of those not treated with this medication. 152
The administration of an ACE inhibitor may prolong the half-life
of bradykinin, which enables patients to attain a clinically
significant concentration in the plasma; therefore,
it is recommended that ACE inhibitors
be withheld 24 hours before
plasmapheresis
WHEN AND HOW

CONCLUSION
 The use of plasmapheresis to treat a variety of kidney
diseases has expanded significantlysince the 1990s. In
some cases, the rationale and benefitare supported by
data from clinical studies, but in many cases, the
benefitsare not well established. Nevertheless, the
rationale of removing plasmacontaining pathogenic
antibodies is now well established. Additionalstudies
are needed to determine the potential benefits for
plasmapheresis in these other conditions
WHEN AND HOW

Conclusion
 In the earlydays, the utility of plasmapheresiswas
judged on the basis of anecdotal or uncontrolled
studies; more recently, the number of clinical
indications for plasmapheresis has been growing.
However, the number of clinical conditions that have
been rigorously studied with prospectiveand
randomized controlled trials remains small, and
decisions for the implementationof plasmapheresis
(an invasiveand potentiallydangerous procedure) are
still based on results of anecdotal and uncontrolled
studies in many circumstances
WHEN AND HOW

refferences
 Buhaescu I., Covic A., and Levy J.: Systemic vasculitis: still a challenging disease. Am J Kidney Dis 2005; 46:
pp. 173-185
 De Lind van Wijngaarden R.A., et al: Clinical and histologic determinants of renal outcome in ANCA-
associated vasculitis: a prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol
2006; 17: pp. 2264-2274
 Jayne D.R., et al: Randomized trial of plasma exchange or high dosage methylprednisolone as adjunctive
therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18: pp. 2180-2188
 Bosch X., et al: Treatment of antineutrophil cytoplasmic antibody–associated vasculitis. JAMA 2007; 298: pp.
655-669
 Hattori M., et al: Plasmapheresis as the sole therapy for rapidly progressive Henoch-Schönlein purpura
nephritis in children. Am J Kidney Dis 1999; 33: pp. 427-433
 Walsh M., et al: Rituximab in the treatment of anti–neutrophil cytoplasm antibody associated vasculitis and
systemic lupus erythematosus: past, present and future. Kidney Int 2007; 72: pp. 676-682
 Ferri C., et al: Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231
patients. Semin Arthritis Rheum 2004; 33: pp. 355-374
 Dominguez J.H., and Sha E.: Apheresis in cryoglobulinemia complicating hepatitis C and in other renal
diseases. Ther Apher 2002; 6: pp. 69-76
 Plasmapheresis Madore F.: Technical aspects and indications. Crit Care Clin 2002; 18: pp. 375-392
 Szczepiorkowski Z.M., et al: Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from
the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22: pp. 106-175
 Brenner anr rector 9th edition 2012
WHEN AND HOW

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