110317 purema(r)

PUREMAfi - one step closerto physiological sieving

Dr. Stefan Breiter

MEMBRANA GmbHWuppertal Germany

www.membrana.com

PUREMAfi : Overview

Based on breakthrough process innovation (patented)

A member of the DIAPES fi family, polymer: polyethersulfone

outstanding biocompatibility

renowned clinical records

Unique process technology provides sharpest sieving cu rve (S.E.T.)

new pore forming technology with patent protection

active blood side surface management facilitates to xin removal

highest middle molecular removal (e.g. 2m)

low albumin loss

improved patented bundle makeup P.E.T. fi

LMW removal: performing better than any other synthetic membrane

The PUREMA fi membrane family covers the range from low to super flux

PUREMAfi : New Technology

Unique process technology influences separation profile of membraneformation

thicker separation layer sharpened sieving profile (S.E.T.) optimized dialysate side distribution higher mechanical strength

resulting in

low albumin loss high middle molecule removal maximum low molecular clearance Very high CIS retention

5280

PUREMAfi - Chemical Structure

4533

S

0

0

0

PUREMAfi : polyethersulfone

S

0

0

0

conventional polysulfone

0 C

CH3

CH3

Polysulfone and Polyethersulfone

Polysulfone and Polyethersulfone are given trivial nam es forsubstances from the same class (polyethers, polysulfones )

chemically, both are very similar

minor differences in hydrophilicity, mechanical and th ermal stability

generally different production principles of the basicpolymer

both are equally suitable as membrane materials

similar production prinicples of the membranes

minute, but decisive differences from manufacturer to manufacturer

Cross Section of Different MembranesPolysulfonAPS

PolyfluxPUREMAfi

1069

Coreliquid

Polymersolution Cross-section view

Polymer spinningsolution

Core liquid

Spinneret

make-up

winding cutting

wrapping of capillary bundles

PUREMAfi Production Process

membraneformation

pre-extraction

S.E.T. washing drying

4695

PET (Poly Ethylene Terephthalate) spacer yarns consist of multifilament threadsintegrated into the fiber bundles

Improves dialysate distribution throughout the dialyzer

Increases clearance values

Maintains consistent performance throughout the entire treatment from dialyser to dialyser

0319

P.E.T.fi : Performance Enhancing Technology

Comparison of Bundle Make Up I

Fresenius F-series DIAPES fi Gambro Polyflux S-series

0969

Comparison of Bundle Make Up II

Fresenius Optiflux-series PUREMA fi Gambro Polyflux L-series

0970

PUREMAfi H

1065

PUREMAfi : highest LMW Clearancein vitro Benchmark

220

230

240

250

260

270

280

290

300

1 1,2 1,4 1,6 1,8 2 2,2

Surface area [m]

PUREMAfi HFXOptifluxPolyflux HFPolyflux SAPS

5270

Ure

a cl

eara

nce

[ml/m

in]

QB 300 [ml/min]

PUREMAfi

Fesenius FX-SeriesFresenius Optiflux fi

Gambro Polyflux fi HFresenius F-SeriesGambro Polyflux fi SAsahi Polysulfone

PUREMAfi : Stable Low Molecular Clearance

QB = 300 ml/minQD = 500 ml/min8 patients

Clinical Study, March 2005

* p< 0.0530 min vs. 240 min

5524

*

0

50

100

150

200

250

300

Urea Creatinine Phosphate

Cle

ara

nce

[ m

l / m

in ]

30 min.

240 min.*

S.E.T.

S.E.T. stands for Sieving Enhancing Technology

unique patented process technology

1. thicker separation layer

2. unchanged ultrafiltration

3. more uniform pore distribution

4. active surface management

steeper sieving curve

more selective removal

5525

PUREMAfi H: Uniform Pore Size Distribution

cross-section outer surface inner surface

first generation PES membrane

PUREMAfi

sepa

ratio

nla

yer

1072

S.E.T. Sieving Enhancing TechnologyPore Size Distribution

5282

PUREMAfi

Conventional Polysulfone

BSA:10,64 nm //// m: 8,28 nm2-m: 5,94 nmInulin:4,60 nmVit. B12: 2,88 nm

pore size

%

PUREMA H

Fresenius FX

Poly flux S

PUREMAfi H sieving curve

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

100 1000 10000 100000

Molecular Weight [Dalton]

SC PUREMA(R) H

FMC FX

Optiflux

Human Kidney

Polyflux H

S.E.T. Sieving enhancing technology:active surface management

during the production process, active centres are createdon the blood side (patent protected technology)

these active centres mediate the electrostatic, polar an d hydrophobic interactions of proteins and middle molecul artoxins with the membrane wall

protein adsorption to the membrane and the pores isreduced (reduced clogging)

middle molecular toxins can move more easily through thepores

unprecedented removal characteristics

S.E.T. Active Surface ManagementPUREMAfi Blood Side Surface

red: hydrophobicdomains (PES)

green: hydrophilicdomains (PVP)

blue: active centre

1268

PUREMAfi : Visibly Reduced Protein Adsorption

1300

Polyamix Polysulfone FXPUREMAfi

Protein adsorption visualised with fluorescent 2m

PUREMAfi H Reduced Protein AdsorptionAdsorption of Radioactive Labelled Albumin

5598

0

1

2

3

4

5

6

7

8

9

10

11

Purema H Purema H without S.E.T . Polyflux H140 Polysul fon FX60

Alb

um

in A

dso

rptio

n / u

nits

PUREMAfi H PUREMAfi H

SC Profile of PUREMA fi Compared to Other SyntheticMembranes

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Cytochrome C

siev

ing

coef

ficie

nt

PUREMAfi

Fresenius F-series

Fresenius FX-series

Fresenius Optiflux-series

Gambro Polyflux H-series

0

0,005

0,01

0,015

0,02

BSA

siev

ing

coef

ficie

nt

PUREMAfi

Fresenius F-series

Fresenius FX-series

Fresenius Optiflux-series

Gambro Polyflux H-series

In vitro testing in minimodules5% BSA in PBSQB 200 ml/ min mQF 30 ml/ min m

5276

2M Removal

5526

Clinical Studies, July 2004 / March 2005


* p< 0.05PUREMAfi H vs. FX80and 170H

* *

0

10

20

30

40

50

60

70

80

90

100

corrected by hematocrit corrected according to Bergs trm-Wehle

2M

- r

emo

val R

atio

[ %

]

Polysulfon FX80

Purema H

Polyflux 170 H

Polysulfone FX80, 1.8mPUREMAfi H, 1.7mPolyflux 170H, 1.7m

* *

PUREMAfi :Consistently high 2M Clearance Over Time



* *


****

** p< 0.0530 min vs. 240 min

0

20

40

60

80

100

120

140

160

30 min 240 min

2M

- C

lea

ranc

e [

ml /

min

]

Polysulfon FX80

Purema H

Polyflux 170 H


* *

* ** *

Albumin Removal



0

0,5

1

1,5

2

2,5

3

Alb

umin

in d

ialy

sate

[g /

4h]

Polysulfon FX80

Purema H

Polyflux 170H


Cystatin C Removal




* *

0

10

20

30

40

50

60

70

80

corrected by hematocrit corrected according to Bergs trm-Wehle

Cys

tatin

C -

Rem

ova

l Ra

tio [

% ]

Polysulfon FX80

Purema HPolyflux 170 H


* *

Cystatin C Clearance


0

20

40

60

80

100

120

140

30 min 240 min

Cys

tatin

C -

Cle

aran

ce [m

l/min

]

Polysulfon FX80Purema HPolyflux 170 H



** p< 0.05vs. FX80 and 170H

* p< 0.0530 min vs. 240 min

*

*** **

*

0

20

40

60

80

100

120

140

30 min 240 min

Cys

tatin

C -

Cle

aran

ce [m

l/min

]

Polysulfon FX80Purema HPolyflux 170 H



** p< 0.05vs. FX80 and 170H

* p< 0.0530 min vs. 240 min

*

*** **

*

Myoglobin Removal

Clinical Study, March 20055532

0

10

20

30

40

50

60

70

80

corrected by hematocrit corrected according toBergstrm-Wehle

Myo

glob

in -

Rem

oval

Rat

io [%

Polysulfon FX80

Purema H


Polysulfone FX80, 1.8mPUREMAfi H, 1.7m

*

* p< 0.05vs. FX80

*

0

10

20

30

40

50

60

70

80

corrected by hematocrit corrected according toBergstrm-Wehle

Myo

glob

in -

Rem

oval

Rat

io [%

Polysulfon FX80

Purema H



*

* p< 0.05vs. FX80

* QB = 300 ml/minQD = 500 ml/min8 patients


*

* p< 0.05vs. FX80

*

Myoglobin Clearance


0

10

20

30

40

50

60

70

80

30 min 240 min

Myo

glob

in -

Cle

aran

ce [

ml/

min

]

Polysulfon FX80Purema HPolyflux 170H


Polysulfone FX80, 1.8m

PUREMAfi H, 1.7m

Polyflux 170H

0

10

20

30

40

50

60

70

80

30 min 240 min

Myo

glob

in -

Cle

aran

ce [

ml/

min

]

Polysulfon FX80Purema HPolyflux 170H


Polysulfone FX80, 1.8m

PUREMAfi H, 1.7m

Polyflux 170H

PUREMAfi H Separation Profile

5534


-50

-25

0

25

50

75

100

125

150

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000Molecular weight [Da]

30

min

Cle

ara

nce

[ml/m

in]

Polysulfon FX 80

Purema H

Polyflux 170H


Polysulfone FX80, 1.8mPUREMAfi H, 1.7mPolyflux 170H

-50

-25

0

25

50

75

100

125

150

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000Molecular weight [Da]

30

min

Cle

ara

nce

[ml/m

in]

Polysulfon FX 80

Purema H

Polyflux 170H


Polysulfone FX80, 1.8mPUREMAfi H, 1.7mPolyflux 170H

PUREMAfi Biocompatibility:White Blood Cell Count



50

60

70

80

90

100

110

0 30 60 90 120 150 180 210 240

T ime [ min ]

WB

C [

% ]

Polysulfon FX80Polyflux 170HPurema H

Polysulfone FX80, 1.8mPolyflux 170H, 1.7mPUREMAfi H, 1.7m


50

60

70

80

90

100

110

0 30 60 90 120 150 180 210 240

T ime [ min ]

WB

C [

% ]



PUREMAfi Biocompatibility:Complement Activation



0

1

2

3

4

5

6

7

0 30 60 90 120 150 180 210 240

Time [ min ]

C5a

[ g

/l ]




0

1

2

3

4

5

6

7

0 30 60 90 120 150 180 210 240

Time [ min ]

C5a

[ g

/l ]



PUREMAfi Biocompatibility:Platelet Count



50

60

70

80

90

100

110

120

0 30 60 90 120 150 180 210 240

T ime [ min ]

Pla

tele

t Cou

nt [

% ]




50

60

70

80

90

100

110

120

0 30 60 90 120 150 180 210 240

T ime [ min ]

Pla

tele

t Cou

nt [

% ]



PUREMAfi Biocompatibility:Activation of Coagulation



0

2

4

6

8

10

12

14

0 30 60 90 120 150 180 210 240

Time [ min ]

TA

T [

g/l

]




0

2

4

6

8

10

12

14

0 30 60 90 120 150 180 210 240

Time [ min ]

TA

T [

g/l

]



Reduced Mortality Risk in High-efficiency Hemodiafiltration

Canaud B et al., Kidney Int, 69: 2087-2093, 2006

5638

high efficiency (i.e. high volume) HDF has a signif icant survival benefit over HD

it is common sense that this is due to the superior removal of toxins, in particular middle molecules (low mol ecular weight proteins)

in the first clinical studies, PUREMAfi proved its outstanding performance

the 2m clearance and removal found with PUREMAfi in HD corresponds to HDF with replacement volumes exceedi ng 60ml/min with conventional polysulfone membranes

2 -Microglobulin Removal in Online Post-dilution HDF with Conventional High-flux Polysulfone

Lornoy W et al (2000)Nephrol Dial Transplant, 15 (Suppl. 1): 49-555

663

orange line representsperformance of PUREMA fi

in HD in first clinical trials

Clinical study PUREMA fi H in HDvs. competitors in HDF Prospective, cross-over design, 8 patients,

PUREMAfi H (Bellco "Phylther", 1.7 m) in HD

Fresenius HF80S (1.8 m) in postdilution HDF : QS=60ml/min

Gambro Polyflux 170H (1.7 m) in postdilution HDF : QS=60ml/min

QB=300 ml/min, Q D=500-QS ml/min, 240 min

3 treatments (1 week) with each dialyser

Determination of dialyser efficiency

Instantaneous clearances and reduction rates of low -molecular weight proteins

Albumin loss

Low Molecular Clearances (Plasma) 30 Minutes

Clinical Study KSPU0603 October 20065743

0

50

100

150

200

250

Urea Creatinine Phosphate

30 m

in C

lear

ance

[ml/m

in]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

n= 8corrected for surface area

ns

p

2-Microglobulin Plasma Clearance


0

20

40

60

80

100

30 min 180 min

2M

- C

lear

ance

[ml/m

in]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


PUREMAfi H1,7HD

Polysulfone HF80SHDF, QS= 60ml/min

Polyflux 170HHDF, QS= 60ml/min

HD HDF HDF HD HDF HDF

n.s. n.s.

0

20

40

60

80

100

30 min 180 min

2M

- C

lear

ance

[ml/m

in]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


PUREMAfi H1,7HD



HD HDF HDF HD HDF HDF

n.s. n.s.

2-Microglobulin - Removal Rate


0

10

20

30

40

50

60

70

80

90

100

Removal Ratio

2M

- R

emov

al R

ate

[%]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

Removal Rate corrected by Bergstrm-Wehle

n= 8

PUREMAfi H1,7HD



p< 0.05 ns

HD HDF HDF0

10

20

30

40

50

60

70

80

90

100

Removal Ratio

2M

- R

emov

al R

ate

[%]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


n= 8

PUREMAfi H1,7HD



p< 0.05 ns

HD HDF HDF

for comparison: 2-Microglobulin Plasma Clearance for all membranes in HD mode


0

20

40

60

80

100

30 min 180 min

2M

- C

lear

ance

[m

l/min

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


PUREMAfi H1,7HD

Polysulfone HF80SHD, QS= 0ml/min

Polyflux 170HHD, QS= 0ml/min

p< 0.05

p< 0.05

p< 0.05

p< 0.05

p< 0.05

HD HD HD HD HD HD0

20

40

60

80

100

30 min 180 min

2M

- C

lear

ance

[m

l/min

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


PUREMAfi H1,7HD

Polysulfone HF80SHD, QS= 0ml/min

Polyflux 170HHD, QS= 0ml/min

p< 0.05

p< 0.05

p< 0.05

p< 0.05

p< 0.05

HD HD HD HD HD HD

Cystatin C - Removal Rate


0

10

20

30

40

50

60

70

80

RR by BW

Cys

tatin

C -

Rem

oval

Rat

e [%

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


n.s.

HD HDF HDF

n= 8

PUREMAfi H1,7HD



0

10

20

30

40

50

60

70

80

RR by BW

Cys

tatin

C -

Rem

oval

Rat

e [%

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


n.s.

HD HDF HDF

n= 8

PUREMAfi H1,7HD



Myoglobin - Removal Rate


0

10

20

30

40

50

60

70

80

RR by BW

Myo

glob

in R

emov

al R

atio

[%]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


p< 0.05

p< 0.05

HD HDF HDF

n= 8

PUREMAfi H1,7HD



0

10

20

30

40

50

60

70

80

RR by BW

Myo

glob

in R

emov

al R

atio

[%]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H


p< 0.05

p< 0.05

HD HDF HDF

n= 8

PUREMAfi H1,7HD



Retinol Binding Protein - Removal Rate


-20

-10

0

10

20

30

40

50

60

70

RR by BW

RbP

Rem

oval

Rat

e [%

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

HD HDF HDF

n= 8

PUREMAfi H1,7HD




ns ns

-20

-10

0

10

20

30

40

50

60

70

RR by BW

RbP

Rem

oval

Rat

e [%

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

HD HDF HDF

n= 8

PUREMAfi H1,7HD




ns ns

Plasma - 30 min Clearance of Middle Molecules


-50

-25

0

25

50

75

100

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000

Molecular weight [Da]

30 m

in C

lear

ance

[ml/m

in]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

PUREMAfi H1,7HD



n= 8 2m CyC

Myo

RbP

-50

-25

0

25

50

75

100

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000


30 m

in C

lear

ance

[ml/m

in]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

PUREMAfi H1,7HD



n= 8 2m CyC

Myo

RbP

Plasma - 180 min Clearance of Middle Molecules


-50

-25

0

25

50

75

100

125

150

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000


180

min

Cle

aran

ce [m

l/min

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

PUREMAfi H1,7HD



n= 8 2m CyC

MyoRbP

-50

-25

0

25

50

75

100

125

150

11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000


180

min

Cle

aran

ce [m

l/min

]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

PUREMAfi H1,7HD



n= 8 2m CyC

MyoRbP

Albumin in Dialysate


0,0

0,5

1,0

1,5

2,0

Albumin in dialysate

Alb

umin

in d

alys

ate

[g/4

h]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

HD HDF HDF

n= 8

PUREMAfi H1,7HD



ns

ns

0,0

0,5

1,0

1,5

2,0

Albumin in dialysate

Alb

umin

in d

alys

ate

[g/4

h]

PUREMA H1,7

Polysulfone HF80S

Polyflux 170H

HD HDF HDF

n= 8

PUREMAfi H1,7HD



ns

ns

Summary of PUREMA fi H Characteristics in Haemodialysis

Improved biocompatibility with significantly lower complement generation

Significantly enhanced LMW protein removal

Low albumin loss

Steeper sieving profile

PUREMAfi in HD provides LMW protein removal comparabl e to online post-dilution HDF with conventional high- flux membranes

Conclusion

Simple haemodialysis with PUREMAfi H may have beneficial effects on the outcome of maintenance dialysis patients similar to high-efficiency HDF wi th conventional synthetic high-flux membranes .

Summary of PUREMA fi H

a member of the DIAPES(R) family:proven clinical record, renowned biocompatibility

Significantly enhanced LMW protein removal

Low albumin loss

Steeper sieving profile

stable clearance throughout the treatment

Dr. Stefan BreiterScientific Marketing Manager, Healthcare

Membrana GmbHhder Strasse 2842289 Wuppertal

+49 (202) 6099 [email protected]

110317 purema(r)

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