The kinetics of removing largeThe kinetics of removing largemolecules: implications for themolecules: implications for therational prescription of plasmarational prescription of plasma

exchangeexchange

Andre A. Kaplan, MD, FACP, FASNAndre A. Kaplan, MD, FACP, FASNUniversity of Connecticut Health CenterUniversity of Connecticut Health Center

Farmington, CTFarmington, CT

General Guidelines inGeneral Guidelines inPrescribing PlasmapheresisPrescribing Plasmapheresis

Kinetics of Immunoglobulin RemovalKinetics of Immunoglobulin Removal

Kaplan: A Practical Guide to Therapeutic Plasma Exchange, Blackwell Science, 1999

Calculation of Estimated PlasmaVolume (EPV)

EPV = 0.065 x TBW x [1-Hct]

Kaplan: Trans ASAIO 36:M597, 1990

Kaplan & Halley:Kidney Int,38:166, 1990

e -

Kaplan & Halley: Kidney Int, 38:166, 1990

Kaplan & Halley, Kidney Int 38:166, 1990

Samtleben & Gurland 1989

Kaplan: Seminars in Dialysis 5:227, 1992

Kaplan: Seminars in Dialysis 5:227, 1992

Anti-Anti-PhospholipidPhospholipid Antibody Syndrome Antibody Syndrome

Lupus anticoagulant and Lupus anticoagulant and anticardiolipinanticardiolipinantibody associated with arterial andantibody associated with arterial andvenous thrombosis, recurrent fetal loss andvenous thrombosis, recurrent fetal loss andrenal disease.renal disease.

Plasmapheresis has resulted in successfulPlasmapheresis has resulted in successfulpregnancy and reversal of renal disease.pregnancy and reversal of renal disease.Frampton et al. Lancet ii:1023, 1987, Frampton et al. Lancet ii:1023, 1987, FulcherFulcheret al. Lancet ii:171, 1989, Kincaid-Smith et al.et al. Lancet ii:171, 1989, Kincaid-Smith et al.Quart J Med 258:795, 1988Quart J Med 258:795, 1988

Are anti-phospholipid antibodiespathogenic?

Anti-ß2-glycoprotein-I antibodies ß2-GP-I (apolipoprotein H) binds to negatively

charged phospholipids and inhibits both contactactivation of the clotting cascade and theconversion of prothrombin to thrombin.

The properties of this protein as a clotting inhibitormay explain why neutralizing antibodies canpromote thrombosis.

Schousboue I: Blood 1985, 66:1086Nimpf J et al: Biochim Biophys Acta, 1986, 884:142

Are anti-phospholipid antibodiespathogenic?

“Antiphosphospholipid antibodies (aPL) havebeen demonstrated to have procoagulant actionsupon protein C, annexin V, platelets, serumproteases, toll-like receptors, tissue factor, andvia impaired fibrinolysis.

Aside from increasing the risk of vascularthrombosis, aPL increase vascular tone, therebyincreasing the susceptibility to atherosclerosis,fetal loss and neurological damage.”

BL Bermas, PH Schur, UpToDate, 2010

Catastrophic Catastrophic AntiphospholipidAntiphospholipid Antibody AntibodySyndrome (CAPS)Syndrome (CAPS)

CAPS is a rare life-threatening form ofCAPS is a rare life-threatening form ofantiphospholipidantiphospholipid antibody syndrome antibody syndrome(APS) with (APS) with multiorganmultiorgan involvement involvement

Associated mortality rate is >50%.Associated mortality rate is >50%.

Treatment consists of IV heparin, IVTreatment consists of IV heparin, IVsteroids, IVIG and/or TPEsteroids, IVIG and/or TPE..

Catastrophic Catastrophic AntiphospholipidAntiphospholipid Antibody AntibodySyndrome: Case ReportSyndrome: Case Report

33 year old female with history of primary APS with multiple33 year old female with history of primary APS with multiplemiscarriages and deep venous thrombosismiscarriages and deep venous thrombosis

Presented with headaches and visual field defects.Presented with headaches and visual field defects. Non-compliance with Non-compliance with coumadincoumadin. INR was 1.3.. INR was 1.3.

Patient presents with AKI and myocardial infarction. SerumPatient presents with AKI and myocardial infarction. Serumcreatininecreatinine ( (S.CrS.Cr) peaked at 2.8 mg/dl by the third day.) peaked at 2.8 mg/dl by the third day.

Transferred to ICU and started on IV heparin.Transferred to ICU and started on IV heparin.

Within 24 hours of admission, her mental status deteriorated andWithin 24 hours of admission, her mental status deteriorated andshe developed seizures and left sided she developed seizures and left sided hemiplegiahemiplegia. She. Shesubsequently developed malignant hypertension (BP 225/130subsequently developed malignant hypertension (BP 225/130mmHg), flash pulmonary edema and required intubationmmHg), flash pulmonary edema and required intubation

MRI inpatient withCAPS

Anticardiolipin antibody removal by TPE

0

10

20

30

40

50

60

70

TPE treatments

Imm

unoglo

bulin

Concentr

ation (

mg/d

l)

IgM aCL AB IgG aCL AB Zar & Kaplan: Clin Nephrol, 70:77, 2008

Observed and predicted decline in IgG anticardiolipinantibody.

DayaCL IgG (u/ml) Ve

(ml)EPV Ve/EPV

(ml)% decline in aCLIgG

Pre Post Expected Achieved

#1 56 27 4000 3682 1.08 66 51.7

25 11 4000 3574 1.11 67 56.0

#2 19 6 4000 3549 1.07 66 68.4

#3 13 5 4000 3603 1.11 67 61.5

#4 10 4 4000 3648 1.09 66 60.0

#5 9 3 4000 3648 1.09 66 66.6

T. Zar & A. Kaplan. Clin Nephrol, 70:77, 2008

Observed and predicted decline in IgM anticardiolipin

DayaCL IgM(u/ml)

Ve(ml)

EPV(ml)

Ve/EPV % decline in aCLIgM

Pre Post Expected Achieved

#1 59 23 4000 3682 1.08 66 61.0

23 11 4000 3574 1.11 67 52.1

#2 17 8 4000 3549 1.07 66 52.9

#3 9 4 4000 3603 1.11 67 55.5

#4 9 4 4000 3648 1.09 66 55.5

#5 8 3 4000 3648 1.09 66 62.5

T. Zar & A. Kaplan. Clin Nephrol, 70:77, 2008

TPE for CAPS

CAPS has never been investigated in aprospective, randomized trial but a review ofthe first 250 patients entered into the CAPSRegistry demonstrated that the combination ofTPE, anticoagulants and steroids wasassociated with an overall 78% survivalleading the authors to conclude that thistreatment combination should be the first lineof therapy for patients with CAPS

Bucciarelli S. et al. Arthritis Rheum 2006;54:2568

ApheresisApheresis for Renal Disease for Renal Disease

Primary Renal DiseasePrimary Renal Disease GoodpastureGoodpasture’’ss disease disease

IgAIgA nephritis/HSP nephritis/HSP

PauciPauci-immune RPGN-immune RPGN

Focal segmentalFocal segmentalglomerulosclerosisglomerulosclerosis

Secondary Renal DiseaseSecondary Renal Disease SLESLE

APA syndromeAPA syndrome

CryoglobulinemiaCryoglobulinemia

Multiple MyelomaMultiple Myeloma

TTP/HUSTTP/HUS

TransplantationTransplantation

Rapidly Progressive Rapidly Progressive GlomerulonephritisGlomerulonephritis

Anti-GBM

Post-StrepS.B.E.Lupus

IgACryoglobulines

Membrano-Proliferative

Immune-Complex

Wegener'sPANIdiopathic

Pauci-Immune

RPGN

Anti-GBM Antibody andAnti-GBM Antibody andGoodpastureGoodpasture’’ss Syndrome Syndrome

Pathogenic antibody capable of causingPathogenic antibody capable of causingalveolar hemorrhage and rapidlyalveolar hemorrhage and rapidlyprogressive progressive glomerulonephritisglomerulonephritis

Only one randomized, controlled trial:Only one randomized, controlled trial:Johnson et al. Medicine 64:219, 1985Johnson et al. Medicine 64:219, 1985

Plasmapheresis results in rapid lowering ofPlasmapheresis results in rapid lowering ofanti-GBM antibody, lower post RXanti-GBM antibody, lower post RXcreatininecreatinine and reduced incidence of ESRD and reduced incidence of ESRD

Lockwood et al. Br Med J 1975;2:252

Anti-GBM ANTIBODY DISEASE &GOODPASTURE’S SYNDROME

Rapidly Progressive Rapidly Progressive GlomerulonephritisGlomerulonephritis

Anti-GBM

Post-StrepS.B.E.Lupus

IgACryoglobulines

Membrano-Proliferative

Immune-Complex

Wegener'sPANIdiopathic

Pauci-Immune

RPGN

CryoglobulinemiaCryoglobulinemia

Despite lack of randomized, controlledDespite lack of randomized, controlledtrials, there is a general consensus thattrials, there is a general consensus thatplasmapheresis is useful for rapid removalplasmapheresis is useful for rapid removalof of cryoglobulinscryoglobulins..

ConcomittantConcomittant hepatitis C infection may hepatitis C infection mayrender chemotherapy problematic.render chemotherapy problematic.

Some patients may respond toSome patients may respond toplasmapheresis alone. plasmapheresis alone. FerriFerri et al. et al. NephronNephron43, 246, 198643, 246, 1986

Cryoglobulin Removal with TherapeuticPlasma Exchange (TPE)

DATE IgM

mg/dL

Crycrit %

Day 1 pre TPE

post TPE

294

97

8%

Day 2 pre TPE

post TPE

119

61 trace

Hepatitis C associated cryoglobulinemiapresenting with RPGN eight months aftersuccessful suppression of viral load withinterferon

Creat

mg/dL

WaldenstromWaldenstrom’’ssMacroglobulinemiaMacroglobulinemia

FunduscopicFunduscopic abnormalities abnormalitiesin in hyperviscosityhyperviscositysyndrome include dilatedsyndrome include dilatedand tortuous retinal veins,and tortuous retinal veins,giving a "sausage link"giving a "sausage link"appearance(8)appearance(8)

Other retinal lesionsOther retinal lesionsinclude hemorrhages,include hemorrhages,exudates and exudates and papilledemapapilledema

Clinical Manifestations of Clinical Manifestations of WaldenstromWaldenstrom’’ss MacroglobulinemiaMacroglobulinemiaGarcia-Garcia-SanzSanz R et al. Br J R et al. Br J HaematolHaematol 2001 Dec;115(3):575-82 2001 Dec;115(3):575-82

Anemia/fatigue 80%Anemia/fatigue 80%

Bleeding 23%Bleeding 23%

Fevers, Night sweats, Weight loss: 23%Fevers, Night sweats, Weight loss: 23%

Neurologic symptoms 27%Neurologic symptoms 27%

Distal, symmetric, and slowly progressive Distal, symmetric, and slowly progressive sensorimotorsensorimotor peripheral peripheralneuropathy causing neuropathy causing paresthesiasparesthesias and weakness and weakness

LymphadenopathyLymphadenopathy 40%, 40%, hepatomegalyhepatomegaly or splenomegaly30%, and or splenomegaly30%, andhepatosplenomegaly(25%)hepatosplenomegaly(25%)

HyperviscosityHyperviscosity related symptoms due to increased levels of related symptoms due to increased levels ofIgMIgM (31%) (31%)

Loss or blurring of vision, Loss or blurring of vision, nystagmusnystagmus, ataxia, tinnitus,, ataxia, tinnitus,sudden deafness, sudden deafness, diplopiadiplopia, vertigo, headache, dizziness, vertigo, headache, dizziness

MW: 900,000 daltons

DateDate IgMIgM

Mg/dlMg/dlViscosity (1.1-Viscosity (1.1-1.8 1.8 centipoisecentipoise))

Day 1Day 1

TpeTpe 1 158875887

314131414.224.22

2.22.2

Day 2Day 2

TpeTpe 2/ 2/RituxmabRituxmab

38933893

164416442.172.17

1.521.52

Day 3Day 3 26902690 1.61.6

Day 5Day 5

TpeTpe 3 340744074

174817482.712.71

1.411.41

Day 6Day 6

TpeTpe 4 423782378

120412041.651.65

1.131.13

Day 7Day 7 19941994 1.361.36

IgM 1200-2300 mg/dL, viscosity 2.2 (n < 1.8)

TPE for Hyperlipidemia

Turnberg, Gut 13:1972

Lipid apheresis forprimary biliarycirrhosis

Kaplan: Trans ASAIO 36, 1990

Single plasma volume exchange in Primary Biliary Cirrhosis

0

50

100

150

200

250

300

350

AST ALT TRIGLYC T. CHOL T.BILI D. BILI

pre treatment post treatment(values x 10)

Lancet:1208-11,1975

Lancet i:1208-1211, 1975

Thompson et al. Br Med J, 291:1671,1985

TPE treated patients survived a mean 5.5 years longer than untreated siblings

Thompson et al. Br Med J, 291:1671-1672, 1985

Case report: Familial homozygotichypercholesterolemia

s/p orthotopic heart transplant x 1 year

meds: cyclosporine, prednisone, imuran,lasix, quinine, bactrim, nystatin, digoxin,calcium, lipitor, didronel, premarin,provera

61 year old female

Cholesterol 489 mg/dL

Pt#2 pre and post Cholesterol

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

1/

28

/1

99

7

2/

11

/1

99

7

2/

25

/1

99

7

3/

11

/1

99

7

3/

25

/1

99

7

4/

8/

19

97

4/

22

/1

99

7

5/

6/

19

97

5/

20

/1

99

7

6/

3/

19

97

Chol (mg/dL)

Haider & Kaplan

1 weekinterval

2 weekinterval

1 weekinterval

050100150200250300350400

7/1/2003

9/1/2003

11/1/2003

1/1/2004

3/1/2004

5/1/2004

7/1/2004

LDL(md/dL)

Pt#1 Pre and Post LDL (mg/dL)

Haider & Kaplan

In Summary:

Removal of large molecules from the intravascularspace follows first order kinetics analogous to theKT/V prescription for urea

In general, a single plasma volume exchange lowersintravascular levels by 65%

After a single treatment, there is a slow equilibrationfrom the extravascular to intravascular space

Scheduling of treatments should account for the halflife of the target and the acuity of its toxicity