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Monash University Malaysia is jointly owned by Monash University and the Jeffrey Cheah Foundation

Does one filter fit all?

Dr Rafidah Atan,

Senior Lecturer and Intensivist

Clinical School Johor Bahru, Monash University Malaysia


Overview

History of filter development

Filter terminology

Differences between earlier filters and current filters

One filter for all?

Experimental filters


First case of human dialysis

1924

By Georg Haas in Germany

Uraemic patient – for 15 minutes

Membrane used: Collodian – cellulose trinitrate


First dialysis for acute renal failure

1943

By Willem Kolff in Netherlands

Cellophane – also cellulose derived - came into the market in 1937


The earliest filters were cellulose

derivatives:

1924 - Collodian (cellulose nitrate)

1937 - Cellophane membrane (dominated market for 20 years)

1964 - Cellulose acetate

1967 – Cuprophane


Earlier filters: The problem with cellulose

Cellubiose contains hydroxyl group (OH)

Complement activation, inflammatory response and cytokine induction

Led to dialysis symptoms and intolerance – long term effects ?dialytic

cachexia

Manufacturers – substituted –OH group e.g. with acetate (cellulose

acetate, cellulose diacetate, cellulose triacetate) or other moieties

(Haemophan) but problem not eliminated completely

Cellulose derived membranes also known as “Bioincompatible

membranes” (BICM)


Earlier filters: The issue of ‘flux’

Earlier dialyzers were low flux

Definition of flux:

1) Rate of water passing through for a given transmembrane pressure

(Ultrafiltration coefficient)

Low flux - < 10 ml/min per mmHg, high flux >20 ml/min per mmHg

Low flux - not suitable for convection (haemofiltration)

2) The MW of molecules that pass through the membrane

Low flux – poor removal of B2 microglobulin. Amyloidosis in long-term

dialysis.


Earlier filters: Membrane technology

Earlier membranes were flat-sheet technology

Sheets of membrane stacked in multiple layers


Membrane technology: Hollow fibre

1967 – „hollow fiber‟ membrane (ultrathin capillary fibers) designed


Hollow fibre membranes

Thousands of capillary fibres

Stable at high transmembrane pressures

Best combination of low priming volume and high surface area


Hemofiltration

First clinical hemofiltration in 1975 by Henderson

Use of transmembrane pressure to drive convection

Not possible to use Cuprophane – low flux – bursts when subjected to

transmembrane pressure

Amicon XM50 (polysulfone) – high-flux and hollow fibre device


Current filters

Largely high flux, hollow fibre membranes

Synthetic material:

Polysulfone

Polyacrylonitrile (PAN)/ AN69 (copolymer of acrylonitrile and sodium

methallylsulfonate)

Polyamide

Polymethylmethacrylate (PMMA)

Known as “Biocompatible membranes”

Low flux variants are also available


Bioincompatible vs. biocompatible

Bioincompatible membranes – complement activation, cytokine

induction, platelet activation

Cellulose derived vs. synthetic?

The above has been disputed – different filters may have different

biological effects, both synthetic and cellulose derived


Bioincompatible (BICM) vs. biocompatible

(BCM)

A number of papers available in the literature

Outcomes: Mortality and renal recovery

Conflicting results


Bioincompatible (BICM) vs. biocompatible

(BCM)

Benefit

Hakim 1994

Himmelfarb 1998

Schiffl 1994

Schiffl 1995

No benefit

Albright 2000

Assouad 1996

Gastaldello 2000

Jorres 1999

Kurtal 1995

Metaanalyses - conflicting results


Cochrane review

Intermittent haemodialysis for

acute renal failure

BICM vs. BCM

RR mortality 0.93 (0.81 to 1.07)

RR renal recovery 1.09 (0.9 to

1.3)

No clinical benefit of BCM over

BICM


KDIGO section on membranes

5.5.1: We suggest to use dialyzers with a biocompatible membrane for

IHD and CRRT in patients with AKI. (2C)


Relevance to us?

Not a big issue

Haemofiltration (CVVH, CVVHDf): require high flux membranes which

are all synthetic

IHD including hybrid therapies (SLED): almost 100% synthetic

membranes, except some small chronic dialysis centres


Synthetic membranes are all the same?


Specific issues: AN69

Highly negatively charged

Activation of Hageman Factor (Factor XII) - production of bradykinins –

anaphylactoid reactions

Of greater concern in patients on ACE inhibitors – blocks catabolism of

bradykinins

Tielemans C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem JL.

Anaphylactoid reactions during hemodialysis on AN69 membranes in patients

receiving ACE inhibitors. Kidney Int. 1990 Nov;38(5):982-4



Also in reported in patients who are not on ACE inhibitors

Schaefer RM, Fink E, Schaefer L, Barkhausen R, Kulzer P, Heidland A. Role of

bradykinin in anaphylactoid reactions during hemodialysis with AN69 dialyzers. Am

J Nephrol. 1993;13(6):473-7.



Reported in patients on angiotensin receptor blockers

Reported in patients on continuous venovenous haemofiltration (CVVH)

John B, Anijeet HK, Ahmad R. Anaphylactic reaction during haemodialysis on

AN69 membrane in a patient receiving angiotensin II receptor antagonist. Nephrol

Dial Transplant. 2001 Sep;16(9):1955-6

Kammerl MC, Schaefer RM, Schweda F, Schreiber M, Riegger GA, Krämer BK.

Extracorporal therapy with AN69 membranes in combination with ACE inhibition

causing severe anaphylactoid reactions: still a current problem? Clin Nephrol.

2000 Jun;53(6):486-8.


AN69ST

ST = surface treated

Reduced electronegativity – reduced bradykinin

Patients successfully dialyzed while taking ACE-inhibitors, despite

previous reactions

Has heparin-coated version (Oxiris)


Relevance to us?

Just a cautionary note in guidelines (including KDIGO and UpToDate)

in patients on ACE inhibitors

Anaphylactoid reactions have also be attributed to other factors such as

sterilisation method (ethylene oxide), priming with acidic blood,

reprocessing technique

Anaphylactoid reactions also reported with reused polysulfone and

cellulose acetate

AN69ST (surface treated) – largely reduces occurrence


Other differences?


Hemofilters for adsorption of cytokines?

Different membranes have different capacity for adsorption

Overall:

AN69, PMMA – claim good adsorption of cytokines

Polysulfone – conflicting reports

Polyamide – poor adsorption



2 in 1?

Experimental evidence exists – cytokine clearance, plasma cytokines,

surrogate outcomes

Bouman CS, van Olden RW, Stoutenbeek CP. Cytokine filtration and adsorption

during pre- and postdilution hemofiltration in four different membranes. Blood

Purif. 1998;16(5):261-8.



Issues:

- membranes not designed primarily for adsorption - ?quick saturation

- potentially released back into the circulation

- no evidence to support benefit of cytokine adsorption even by

adsorption devices

Largely experimental – no evidence to support superiority of

membranes based on this


Haemofilters for filtration of cytokines?

Standard high flux filters generally poor at removing cytokines

Atan R, Crosbie D, Bellomo R. Techniques of extracorporeal cytokine removal: a

systematic review of the literature. Blood Purif. 2012;33(1-3):88-100


Diffusion and the flux issue

iHD and SLED – mainly high flux synthetic membrane although low flux

variant still available

Preferable in achieving clearance of 2 microglobulin in long-term CKD

patients

High flux – issue of backfiltration if water quality is poor


‘Backfiltration’ in dialysis

Movement of impurities from dialysate to blood

Risk with high flux filters because of high membrane permeability

If water source sterility is an issue, recommendation is to use low flux

filters


Synthetic membrane overview

Almost 100% use of high flux variety

No membrane is specifically superior

Some caution on AN69 in patients on ACE-inhibitors

Some caution in dialysis using high flux filters if water quality poor

No evidence to support adsorption or cytokine removal by standard

hemofilters


Super high flux filters

High cut-off filters

Larger pore size = higher „cut-off point‟

Cut-off point of 60kDa = 10% of molecules with MW 60kDa will pass

through the filter


Standard filters (high flux filters)

Nominal cut off: 30 kDa

When exposed to blood, effective pore size is 15 to 20 kDa

(membrane fouling)

28th February 2011 Presentation title 34



„Super high-flux hemofilters‟

Pore size 60 to 150kDa: in-vivo ~ 60kDa

Filter can be used with all standard techniques: CVVH,

CVVHDf, CVVHD


Boschetti-de-Fierro A, Voigt M, Storr M, Krause B. Extended characterization of a new class of membranes for

blood purification: the high cut-off membranes. Int J Artif Organs. 2013 Jul;36(7):455-63.


Standard filters

High flux filters

Pore size: 30 kDa

When exposed to blood,

effective pore size is 15 to

20 kDa


Super high flux

Pore size: 65 to 150 kDa

When exposed to blood,

effective pore size ~ 60 kDa



High cut-off (super high flux) filters

Cut-off point of native kidney is 65 kDa

Designed to improve removal of middle molecules e.g. cytokines

Systematic review on technical performance – better cytokine removal

by high cut-off filters

Clinical benefit of cytokine removal – no evidence thus far

Atan R, Crosbie D, Bellomo R. Techniques of extracorporeal cytokine removal: a

systematic review of the literature. Blood Purif. 2012;33(1-3):88-100


High cut-off filters in multiple myeloma

50% of myeloma patients develop cast nephropathy and AKI

Free light chains filtration at the glomerulus

Treatment - rapidly reduce free light chains in the circulation


Reduction of circulating free light chains

Achieved by chemotherapy and plasma exchange

Plasma exchange – improvement in small trials but large RCT no

benefit

High cut-off dialysis – ? reduced dialysis dependence

Tan J, Lam-Po-Tang M, Hutchison CA, de Zoysa JR. Extended high cut-off

haemodialysis for myeloma cast nephropathy in Auckland, 2008-2012. Nephrology

(Carlton). 2014 Jul;19(7):432-5.

Borrego-Hinojosa J, Pérez-del Barrio MP, Biechy-Baldan Mdel M, Merino-García

E, Sánchez-Perales MC, García-Cortés MJ, Ocaña-Pérez E, Gutiérrez-Rivas P,

Liébana-Cañada A. Treatment by long haemodialysis sessions with high cut-off

filters in myeloma cast nephropathy: our experience. Nefrologia.

2013;33(4):515-23


Two European RCTs currently ongoing


High cut-off filter for rhabdomyolysis?

A few postulated mechanism of AKI in rhabdomyolysis – reduction in

circulating myoglobin may be beneficial

MW of myoglobin is 17 kDa but electrically charged and asymmetrical –

need larger pores

Clearance by dialysis - poor

Clearance by standard hemofiltration – controversial results

Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis

-- an overview for clinicians. Crit Care. 2005 Apr;9(2):158-69.

Ronco C. Extracorporeal therapies in acute rhabdomyolysis and myoglobin

clearance. Crit Care. 2005 Apr;9(2):141-2.


High cut-off filter and rhabdomyolysis

First reported in 2005 by Naka et al

Reported five times higher myoglobin concentration in filtrate compared

to standard (high flux) filter

Naka T, Jones D, Baldwin I, Fealy N, Bates S, Goehl H, Morgera S, Neumayer HH,

Bellomo R. Myoglobin clearance by super high-flux hemofiltration in a case of

severe rhabdomyolysis: a case report. Crit Care. 2005 Apr;9(2):R90-5


Naka et al

No change in serum myoglobin levels with standard filters

Rapid drop with high cut-off filters

Naka T, Jones D, Baldwin I, Fealy N, Bates S, Goehl H, Morgera S, Neumayer HH,

Bellomo R. Myoglobin clearance by super high-flux hemofiltration in a case of

severe rhabdomyolysis: a case report. Crit Care. 2005 Apr;9(2):R90-5


High cut-off filter and rhabdomyolysis

Case reports - both haemofiltration and dialysis techniques used

RCT ongoing – surrogate outcome

Current recommendations for rhabdomyolysis is still volume expansion

Heyne N, Guthoff M, Krieger J, Haap M, Häring HU. High cut-off renal

replacement therapy for removal of myoglobin in severe rhabdomyolysis and acute

kidney injury: a case series. Nephron Clin Pract. 2012;121(3-4):c159-64

Wu B, Gong D, Ji D, Xu B, Liu Z. Clearance of myoglobin by high cutoff

continuous veno-venous hemodialysis in a patient with rhabdomyolysis: a case

report. Hemodial Int. 2015 Jan;19(1):135-40


Relevance to us?

Use in multiple myeloma is well known

Use in rhabdomyolysis not as widespread

Both indications have not received specific recommendations


Experimental devices – bioartificial

kidneys (BAK)

Renal assist device (RAD)

Rationale: the kidney is more than a filtration device, kidney cells have

other biological functions

a standard hemofiltration cartridge covered by human renal tubular cells

along the inner surface

Renal cells - transport, metabolic, and endocrinologic activities


Renal assist device (RAD)

Randomised multicenter trial of 58 patients (40 to RAD)

Improved day 28 mortality (RAD vs. conventional CRRT, 33% vs. 61%)

more rapid recovery of kidney function in ICU patients with AKI in the

randomized, multicenter trial

Tumlin J, Wali R, Williams W, Murray P, Tolwani AJ, Vinnikova AK, Szerlip HM,

Ye J, Paganini EP, Dworkin L, Finkel KW, Kraus MA, Humes HD. Efficacy and safety

of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol. 2008

May;19(5):1034-40.


Renal assist device

Experimental

“Wearable device”?


Does one filter fit all - Summary

Almost 100% use of synthetic (BCM) and high flux devices. None

supported by evidence to be superior

Some caution with AN69 types and patients on ACE-inhibitors

Low flux dialyzers still indicated if water quality is poor

High cut-off (super high flux) has been used in cast nephropathy and

rhabdomyolysis

Some experimental devices still being tested


Thank you for your attention

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