PLASMAPHERESIS AND ADSORPTION THERAPIES DE CLERCK.pdf · 2019. 6. 14. · Apheresis < Gr....

PLASMAPHERESIS AND ADSORPTION THERAPIES:

PRINCIPLES, TECHNIQUES, INDICATIONS, PRESCRIPTION, COMPLICATIONS

Dr. Dieter De Clerck 15/06/2019

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OVERVIEW

1. What is plasmapheresis?

2. What is immunoadsorption?

3. Applications of PE and IA in nephrology

4. Quiz

16-03-19 2

Hemodialyse: het succes zit in het access

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PLASMAPHERESIS

Apheresis < Gr. ἀφαίρεσις = taking away

Plasmapheresis = removal of plasma

2 situations:

1. Donation by a healthy donor:

-> Removing a small part of plasma, without need of replacement fluid

2. Therapy: Therapeutic plasma-exchange (TPE):

-> Removing a large part of the plasma, and replacing it by a replacement

fluid, as part of a treatment

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Titel van de presentatie

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DEFINITION

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PLASMAPHERESIS

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OTHER TYPES OF APHERESIS

Winters JL. Plasma exchange: concepts, mechanisms, and an overview of the American Society of Apheresis guidelines. Hematology 2012.

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PLASMA EXCHANGE

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MECHANISM OF ACTION

A) Bulk removal and replacement of plasma

=> 1. removal of pathologic antibodies, immune complexes, cytokines

= major mechanism of action

2. possible immunomodulatory effect

- shift towards Th2

- suppression of IL-2 and IFN-gamma production

B) Replacing a deficient substance, when plasma is used as replacement fluid:

f.i. ADAMTS13 in TTP.

Winters JL. Plasma exchange: concepts, mechanisms, and an overview of the American Society of Apheresis guidelines. Hematology 2012.

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PLASMA EXCHANGE

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TECHNIQUE

1. Separation by density: centrifugation

-> creating layers (RBC, WBC, platelets, plasma):

some platelets may be present in the plasma layer => loss of platelets

2. Separation by size: filtration

-> membrane with pores (~ dialysis)

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PLASMA EXCHANGE

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TECHNIQUE: centrifugation

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PLASMA EXCHANGE

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TECHNIQUE: centrifugation

Different densities:Plasma: 1,025-1,029Platelets: 1,040-1,045Lymphocytes: 1,050-1,061Granulocytes: 1,087-1,092Red blood cells: 1,078-1,114

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PLASMA EXCHANGE

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TECHNIQUE: filtration

www.asahi-kasei.co.jp

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PLASMA EXCHANGE

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TECHNIQUE

Because replacement fluid is administered during PE, plasma is diluted and therefore

substances circulating in the plasma can not be completely removed.

=> For each 1-1,5 plasma volume exchanged, 60-70% of substances present in the

plasma will be removed.

=> Removal of more than 1,5 plasma volume will only remove small amounts of

pathological substance, while prolonging the procedure and increasing the

amount of replacing fluid and anticoagulant.

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PLASMA EXCHANGE

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TECHNIQUE

Brecher M. Plasma Exchange: Why We Do What We Do. Journal of Clinical Apheresis 2002.

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PLASMA EXCHANGE

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PRINCIPLES

Basic principles for removing a substance by PE:

1. It must occur in the blood

2. It must have a molecular weight > 15 kDa or an affinity for plasma proteins. Otherwise

the volume of distribution will be to large and the concentration in the plasma to low

3. Transcapillary escape rate. Some substances stay mainly intravascular (IgM), while

others can pass the capillary wall and are distributed between intravascular and

extravascular (IgG)

-> shift to intravascular during PE: larger amount removed than one should

expect

-> but also re-equilibration after PE

Korsak J and Wánkowicz Z. New Options of Apheresis in Renal Diseases: How and When? Blood Purification 2016.

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PLASMA EXCHANGE

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PLASMA EXCHANGE

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REMOVAL OF NON PATHOGENIC PROTEINS

Because TPE is not selective, both pathologic and normal plasma components will be

removed:

-> Coagulation factors V, VII, VIII, IX, X en VWF activity decline

Return to normal after 4 to 24h

Fibrinogen however after 72h still only at 66%

-> Pseudocholinesterase is removed (-> prolonged neuromuscular blockade)

-> Lab tests may be disturbed => false negative serology for infectious diseases or

auto-antibodies

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DRUG REMOVAL

Ibrahim et al. Drug removal by plasmapheresis. Pharmacotherapy 2007.

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REPLACEMENT FLUIDS

- 4-5% human albumin in NaCl 0,9% (expensive)

- Alternating human albumin with NaCl 0,9% (70% - 30%), with the majority of albumin at

the end of the procedure to avoid hypovolemia (but nevertheless more chance of

hypovolemia compared to albumin alone)

- plasma: limited indications: TTP or preventing coagulopathy; risk of transfusion

reactions and disease transmission

1/3 of the replacement fluid administered at the beginning of the TPE will be present at the

end: when combining albumin and plasma -> plasma at the end

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PLASMA EXCHANGE

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McLeod BC. Plasma and plasma derivatives in therapeutic plasmapheresis. Plasma Transfusion 2012.

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OTHER FORMS OF PLASMA

Cryosupernatant plasma

Removing cryoprecipitate from FFP, removing part of the proteins, notably

the largest VWF multimers

Solvent/detergent plasma

FFP treated with organic solvents and detergents to inactivate lipid-coated

viruses. Relatively deficient in protein C, protein S, alpha2-antiplasmin, alpha1-

antitrypsin, and the largest VWF multimers. Also less allergenicity.

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PLASMA EXCHANGE

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VASCULAR ACCESS

Peripheral veins: maximal blood flow 80ml/’: can be used for centrifugal technique, but is

insufficient for filtration technique (requires blood flow rate of 150-200ml/’)

Filtration requires either central venous access or AV fistula.

Golestaneh L and Mokrzycki M. Vascular Access in Therapeutic Apheresis: Update 2013. Journal of Clinical Apheresis 2013

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ANTICOAGULATION

- Heparin

side effects: bleeding risk, HIT

- Citrate

side effects: hypocalcemia, metabolic alkalosis

Lee G. et al. Anticoagulation Techniques in Apheresis: From Heparin to Citrate and Beyond. J Clini Apher 2012.

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PRESCRIPTION

Estimate of plasmavolume (ml):

Men: [70 X weight(kg)] X [1-Hct] (obese: [60 X weight(kg)] X [1-Hct] )

Women: [65 X weight(kg)] X [1-Hct] (obese: [55 X weight(kg)] X [1-Hct] )

Nadler’s formula:

Men: (0.3669) x height3(m) + (0.3219 x weight(kg)) + 0.6041

Women: (0.3561) x height3(m) + (0.3308 x weight(kg)) + 0.1833

De Back D. et al. Therapeutic plasma apheresis: Expertise and indications. Transfusion and Apheresis Science. 2019.

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PLASMA EXCHANGE

General:

hypotension

infection due to depletion of Ig

bleeding due to depletion of coagulation factors, fibrinogen, antithrombin

hypocalcemia

Related to infusion of plasma:

allergic reactions / anaphylactic reactions

tranfusion-related lung injury (TRALI)

blood transmitted infectious pathogens

Vascular access related complications

=> Monitoring of temperature, blood pressure, heart rate, respiratory rate

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COMPLICATIONS

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Double Filtration Plasmapheresis (DFPP)


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PLASMA EXCHANGE

2 membrane filters:

- plasma separator filters plasma from whole blood

- plasma fractionator differentiates smaller molecular substances from higher

molecular weight proteins: albumin-rich plasma returns to the patient with the

substitution fluid

=> selectively remove macromolecules and reduce the use of substitution fluid

Indication: conditions in which relatively larger molecules in the plasma are responsible for

the pathogenesis, for instance hyperviscosity syndrome in Waldenström’s macroglobulinemia

But: more removal of fibrinogen and therefore higher risk of bleeding

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Double Filtration Plasmapheresis (DFPP) or cascade filtration

Nakanishi et al. Current topics in therapeutic plasmapheresis. Clin Exp Nephrol 2014

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IMMUNOADSORPTION

= technique for clearance of circulating factors, f.i. immunoglobulins, by using an

extracorporal circuit with an adsorption column

Compared to plasma exchange:

- more specific clearance

- no substitution fluid required

- multiple plasma volumes can be processed, hence more effective clearance (>80% of

immunoglobulins)

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Schwenger V and Morath C. Immunoadsoprtion in nephrology and kindey transplantation. NDT 2010.

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IMMUNOADSORPTION

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IMMUNOADSORPTION

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Hamilton P et al. Immunoadsorption Techniques and Its Current Role in the Intensive Care Unit. Aspects in Continuous Renal Replacement Therapy. 2019.

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IMMUNOADSORPTION

Chemical reaction between ligands bound to the surface of the adsorbent and plasma

components.

Ex. Staphylococcal protein A = component of S. aureus cellular membrane

-> extraction of IgG and immune complexes

-> strong affinity for IgG1, IgG2, IgG4; slightly less for IgG3.

Only little affinity for IgM and IgA.

-> binds Fc portion of IgG with greater affinity when complexed to antigen.

Therefore effect in autoimmune disease thanks to removal of immune

complexes containing IgG.

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MECHANISM OF ACTION

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IMMUNOADSORPTION

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Variety on adsorption columns for the same disease (ex. SLE)

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IMMUNOADSORPTION

Leukocytoclastic vasculitis / glomerulonephritis due to Protein A column

-> case reports in RA and ITP

In RA 1,75% of patiënts developped leukocytoclastic vasculitis, 1,25% GN.

In ITP 0,2% leukocytoclastic vasculitis, 0,02% GN.

Mechanism? Activation of inflammation, leakage of SPA, removal of immune complexes

results in increased production of free Ab

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COMPLICATIONS

Iglesias J. Acute glomerulonephritis occurring during immunoadsorption with staphylococcal protein A column (Prosorba). NDT 2004.

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IMMUNOADSORPTION

Specificity has its advantage but, the molecule that is removed by the column needs to be

the proven culprit in every patient (ex. anti-GBM IgA in stead of IgG, different epitopes)

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PITFALL

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APPLICATIONS OF PE AND IA IN NEPHROLOGY

1. TMA

2. Anti-GBM disease

3. Cryoglobulinemia

4. SLE

5. ANCA vasculitis

6. FSGS

7. Transplantation

8. Toxicology

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American Society For Apheresis (ASFA)

=> ASFA GUIDELINES

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PLASMA EXCHANGE

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INDICATIONS

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APPLICATIONS OF PE IN NEPHROLOGY

Clark et al. Plasmapheresis for the treatment of kidney diseases. KI 2016.

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= hemolysis (Coombs -) + thrombopenia + AKI and/or neurological symptoms

take all necessary blood samples

start PE, exchange for plasma

ADAMTS13:

- < 10%: TTP

- > 10%:

- Shigatoxine + : STEC HUS

- Shigatoxine - : SECONDARY TMA versus COMPLEMENT MEDIATED TMA

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1. TMA

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1. TMA

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ASFA:

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1. TMA

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= auto-immune disease with antibodies against NC1 domain of the alpha-3 chain of type IV

collagen of the basal membrane

-> rapidly progressive crescentic glomerulonephritis and/or pulmonary hemorrhage

Very poor renal prognosis if untreated.

Treatment:

- Removal of Ab by PE/IA

- Suppression of production of Ab with immunosuppression (CS, CYC)

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2. Anti-GBM disease

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2. Anti-GBM disease

ASFA:

Urgent start of treatment if there is no dialysis indication at time of diagnosis,

and/or in case of pulmonary hemorrhage.

Very little chance of renal improvement if the patient is dialysis dependent at time

of diagnosis, and if the renal biopsy shows 100% crescents

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Aim: removal of anti-GBM antibodies

Ligand/device: Protein A column (Immunosorba) or IgG column (Therasorb).

Evidence: case report, case series

Biesenbach et al. 2014

IA in 10 patients with anti-GBM: anti-GBM reduced by the first 9 treatments to negative

levels in all patients. Dialysis dependency was succesfully reversed in 3/6 patients (with

100%, 96% and 63% crescent).

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2. Anti-GBM disease:

-> IA

Biesenbach P et al. Long-Term Outcome of Anti-Glomerular Basement Membrane Antibody Disease Treated with Immunoadsorption. PLoS One 2014.

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Presence in the blood of immunoglobulines that precipitate at temperature < 37°.

Vasculitis with glomerulonefritis, skin necrosis, neurological symptoms, arthralgia

Etiology:

- Monoclonal (type 1): multiple myeloma, Waldenström, CLL, MGUS

- Monoclonal + polyclonal (type 2): HCV, HBV, HIV, SLE, Sjögren

- Polyclonal: auto-immune disease, HCV

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3. Cryogblobulinemia

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-> PE can remove circulating cyroglobulins and can be combined with therapy directed

against production of the cryoglobulins.

Indicated in life-threatening or organ-threatening disease:

- severe neuritis

- refractory cutaneous vasculitis

- radidly progressive glomerulonephritis

- symptomatic hyperviscosity

Important: room, lines, replacement fluid should be warmed to prevent

precipitation

-> IA Only evidence from small RCT in HCV related cryoglobulinemia, though

improvement of symptoms and complications

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Auto-immune disease with circulating antibodies (ANA, anti-dsDNA), immune complexes,

complement deposition.

Lupus nephritis with “full house” on biopsy IF.

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4. SLE

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ASFA:

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4. SLE

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-> PE

No evidence to support PE in lupus nephritis.

Some evidence in SLE related TTP, difuse alveolar hemorrhage, myasthenia gravis,

hyperviscosity, cryoglobulinemia, CNS involvement.

-> IA

Case serie: rescue therapy in 11 patients with highly active lupus nephritis with CI or failure

of CYC -> IA with IgG column (Therasorb), 2 sessions within 3 days on clinical demand

during the first year, and every 3 weeks from one year on. Mean of 192 sessions/6,4 years.

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4. SLE

Lewis EJ et al. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. NEJM 1992.Stummvoll et al. Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity. NDT 2012.

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4. SLE

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Consider PE or IA in SLE in

- life threatening disease

- severe refractory kidney disease

- neuropsychiatric involvement

- catastrophic antiphospholipid syndrome

- contraindications to/failure of conventional treatment

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4. SLE

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ANCA associated glomerulonefritis:

-> RPGN (crescents), pauci-immune

-> can be associated with diffuse alveolar hemorrhage

(pulmonary-renal syndome)

ANCA Ab possible pathofysiological role

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5. ANCA vasculitis

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ASFA:

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5. ANCA vasculitis:

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-> PE

MEPEX trial: PE vs IV CS (on top of CS orally + CYC orally) in creat > 5,8mg/dl /dialysis

-> No difference in death; less ESRD at 1 year, but no difference in longer FU

PEXIVAS trial: PE or no PE on top of CYC/RTX + high or low dose CS

-> results (abstract 2018): PE did not make a difference in death or ESRD

-> IA

Swedisch multicentre study:

44 patients with RPGN with crescent (33/44 ANCA), on top of IS treatment, the patients were

randomized between PE and IA (protein A): no difference in outcome.

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5. ANCA vasculitis:

Walsh M et al. Long-term follow-up of patients with severe ANCA associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. KI 2013.Stegmayr BG et al. Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study.. Int J Artif Organs 1999.

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Cause of proteinuria and nephrotic syndrome, with focal areas of sclerosis in some

glomeruli in the renal biopsy.

80% idiopathic: unknown plasmafactor causes injury to the filtration barrier/increases

glomerular permeability.

40% recurrence in kidney transplant (as early as hours/days post transplant)

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6. FSGS

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ASFA:

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6. FSGS

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-> PE

Start as soon as recurrence in transplant is diagnosed.

3 daily exchanges + 6 or more in the next 2 weeks, on top of immunosuppressive treatment

(CS, rituximab).

Long term regimens of weekly to monthly exchanges may be required, depending on the

degree of proteinuria.

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6. FSGS

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-> IA

French pediatric multicentric study:

12 children with recurrence of FSGS within 21d after transplantation were treated with IA,

on top off ACE/ARB, increase in IS, PE.

10/12 responded: 2 partial remission, 8 complete remission. (median respons with UPCR

after 3 sessions)

After 3 months of IA, 2 patients maintained remission without IA.

8 became IA dependent.

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6. FSGS

Allard et al. Treatment by immunoadsorption for recurrent focal segmental glomerulosclerosis after paediatric kidney transplantation: a multicentre French cohort. NDT 2018.

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A) Antibody-mediated rejection

-> PE/IA to remove DSA as part of treatment including IVIG +/- rituximab

(f.i. 5-6 daily or alternate-day exchanges)

B) Transplantation in highly sensitized patients (living donor)

-> desensitization protocols with PE/IA, to remove anti-HLA Ab, including IVIG,

rituximab

(f.i. PE/IA until cross match becomes negative. Transplantation within one

week after last desensitization. Continue PE/IA untill stable graft function.)

C) ABO-incompatible living donor transplantation

-> desensitization protocols with PE/IA including IVIG, splenectomy, rituximab, to

reduce anti-A and anti-B Ab below specific treshold prior to transplantation

(f.i. Rituximab 10 days before transplantation + IA on alternate days before

transplantation + 3 thereafter - Stockholm protocol (Tyden et al))

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7. Transplantation

Tyden G et al. ABO incompatible kidney transplantations without splenectomy, using antigen-specific immunoadsorption and rituximab. Am J Transplant 2005Genberg H et al. Long-term results of ABO-incompatible kidney transplantation with antigen-specific immunoadsorption and rituximab. Transplantation 2007

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Plasma exchange can be applied to remove toxins or in case of drug overdose.

Useful when substances

- are highly plasma protein bound (>80%)

- have a small distribution volume (< 0,2L/kg body weight)

Ex. Amanita Phalloides mushroom intoxication (ASFA Cat II, grade 2C)

Tricyclic antidepressants, l-thyroxine, verapamil, diltiazem, carbamazepin

Some substances bind to other plasmaproteins than to albumin, so exchange for plasma

can be indicated.

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Nenov et al. Current applications of plasmapheresis in clinical toxicology. NDT 2003.

8. Toxicology

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Preeclampsia

Removal of sFlt1 in very preterm preecclampsia (<32w) by IA with a negatively charged

dextran sulfate cellulose column reduces proteinuria and hypertension and prolongation of

pregnancy. PE has also been tried, but results were ambiguous.

Cholesterol Crystal Embolism

Removal of LDL by IA with a dextran sulfate cellulose column (Liposorber) reduces the risk

for maintenance hemodialysis, and a trend towards lower mortality. One might expect the

same results with PE.

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New indications for IA

Kaplan A. Seminars in Dialysis. Novel Uses and Techniques of Therapeutic Apheresis, 2016

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Cost of treatment

Biesenbach P et al. Long-Term Outcome of Anti-Glomerular Basement Membrane Antibody Disease Treated with Immunoadsorption. PLoS One 2014.

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QUIZ

A. IgA

B. IgD

C. IgE

D. IgG

E. IgM

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1. Which antibody will be removed most easily with PE?

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QUIZ

A. Factor V

B. Factor VIII

C. Factor X

D. Antithrombin

E. Fibrinogen

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2. Which member of the coagulation will take longest to normalise

after PE?

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QUIZ

A. Hypotension

B. Allergy

C. Bleeding

D. Hypercalcemia

E. Infection

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3. Which of the following is not a possible complication of PE?

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QUIZ

A. SLE

B. Anti-GBM disease

C. TTP

D. ANCA vasculitis

E. Cryoglobulinemia

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4. In which disease PE with plasma as replacement fluid is indicated?

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QUIZ

A. TMA

B. Dialysisdependent anti-GBM disease with 100% crescents at biopsy and no pulmonary

hemorrhage

C. Type 1 Cryoglobulinemia

D. FSGS recurrence after transplantation

E. SLE complicated by catastrophic antiphoslopid syndrome

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5. In which of the following diseases PE is not indicated?

PLASMAPHERESIS AND ADSORPTION THERAPIES DE CLERCK.pdf · 2019. 6. 14. · Apheresis < Gr....

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