PUREMA - one step closer to physiological sieving

Dr. Stefan Breiter MEMBRANA GmbH Wuppertal Germany www.membrana.com

PUREMA: Overview
Based on breakthrough process innovation (patented) A member of the DIAPES family, polymer: polyethersulfone outstanding biocompatibility renowned clinical records Unique process technology provides sharpest sieving curve (S.E.T.) new pore forming technology with patent protection active blood side surface management facilitates toxin removal highest middle molecular removal (e.g. 2m) low albumin loss improved patented bundle makeup P.E.T. LMW removal: performing better than any other synthetic membrane The PUREMA membrane family covers the range from low to super flux

PUREMA : New Technology

Unique process technology influences separation profile of membrane formation 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

PUREMA - Chemical Structure

0 0
PUREMA: polyethersulfone

S 0

0 0 S 0
conventional polysulfone
4533

CH3 0 C
CH3

Polysulfone and Polyethersulfone

Polysulfone and Polyethersulfone are given trivial names for substances from the same class (polyethers, polysulfones) chemically, both are very similar minor differences in hydrophilicity, mechanical and thermal stability generally different production principles of the basic polymer 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 Membranes

APS Polysulfon

PUREMA

Polyflux

1069

PUREMA Production Process

Polymer solution Core liquid

Cross-section view Polymer spinning solution Core liquid

Spinneret

S.E.T.

washing drying

winding cutting
4695

wrapping of capillary bundles make-up

membrane formation

pre-extraction

P.E.T. : Performance Enhancing Technology

PET (Poly Ethylene Terephthalate) spacer yarns consist of multifilament threads integrated 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

Comparison of Bundle Make Up I

Fresenius F-series

DIAPES

Gambro Polyflux S-series

0969

Comparison of Bundle Make Up II

Fresenius Optiflux-series

PUREMA

Gambro Polyflux L-series

0970

PUREMA H

1065

PUREMA: highest LMW Clearance in vitro Benchmark

300 290 280 270 260 250 240 230
QB 300 [ml/min] PUREMA H PUREMA Fesenius FX-Series FX Optiflux Fresenius Optiflux Polyflux GambroH Polyflux H Fresenius F-Series F GambroS Polyflux S Polyflux APS Asahi Polysulfone

Urea clearance [ml/min]

220 1
5270

1,2

1,4

1,6

1,8

2,2

Surface area [m]

PUREMA: Stable Low Molecular Clearance

300

30 min. 240 min.

250

* *

Clearance [ ml / min ]

200

QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 30 min vs. 240 min

150

100

50

Urea
5524

Creatinine

Phosphate

Clinical Study, March 2005

S.E.T.
S.E.T. stands for Sieving Enhancing Technology unique patented process technology
1. 2. 3. 4.

thicker separation layer unchanged ultrafiltration more uniform pore distribution active surface management steeper sieving curve

5525

more selective removal

PUREMA H: Uniform Pore Size Distribution

first generation PES membrane

separation layer

cross-section

outer surface

inner surface

1072

PUREMA

S.E.T. Sieving Enhancing Technology

Pore Size Distribution
Vit. B12: 2,88 nm Inulin:4,60 nm 2-m: 5,94 nm / m: 8,28 nm BSA:10,64 nm

PUREMA H

Fresenius FX

Polyflux S

PUREMA

5282

pore size

Conventional Polysulfone

PUREMA H sieving curve

1 0,9 0,8 0,7 0,6

SC

0,5 0,4 0,3 0,2 0,1 0 100

PUREMA(R) H FMC FX Optiflux Human Kidney Polyflux H

1000

10000

100000

Molecular Weight [Dalton]

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

during the production process, active centres are created on the blood side (patent protected technology) these active centres mediate the electrostatic, polar and hydrophobic interactions of proteins and middle molecular toxins with the membrane wall protein adsorption to the membrane and the pores is reduced (reduced clogging) middle molecular toxins can move more easily through the pores unprecedented removal characteristics

S.E.T. Active Surface Management PUREMA Blood Side Surface

red: hydrophobic domains (PES) green: hydrophilic domains (PVP) blue: active centre

1268

PUREMA: Visibly Reduced Protein Adsorption

Polyamix

PUREMA

Polysulfone FX

Protein adsorption visualised with fluorescent 2m

1300

PUREMA H Reduced Protein Adsorption

Adsorption of Radioactive Labelled Albumin
11 10 9 Albumin Adsorption / units 8 7 6 5 4 3 2 1 0
PUREMA H PuremaH 5598
H PUREMA Purema H without S.E.T .

Polyflux H140

Polysulfon FX60

SC Profile of PUREMA Compared to Other Synthetic Membranes

1 0,9 0,8 sieving coefficient 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Cytochrome C
sieving coefficient
PUREMA Fresenius F-series Fresenius FX-series Fresenius Optiflux-series Gambro Polyflux H-series

0,02

PUREMA Fresenius F-series Fresenius FX-series

0,015

Fresenius Optiflux-series Gambro Polyflux H-series

0,01

In vitro testing in minimodules 5% BSA in PBS QB 200 ml/ min m QF 30 ml/ min m 5276

0,005

0 BSA

2M Removal

100 90 80

Polysulfon FX80 Polysulfone FX80, 1.8m Purema H H, 1.7m PUREMA

* *

* *

Polyflux 170 H 1.7m Polyflux 170H,

QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 PUREMA H vs. FX80 and 170H

2M - removal Ratio [ % ]

70 60 50 40 30 20 10 0 corrected by hematocrit corrected according to Bergstrm-Wehle

5526

Clinical Studies, July 2004 / March 2005

PUREMA: Consistently high 2M Clearance Over Time

160 140

** * * ** * **

2M - Clearance [ ml / min ]

***

Polysulfon FX80 Polysulfone FX80, 1.8m Purema H H, 1.7m PUREMA Polyflux 170H, Polyflux 170 H 1.7m
QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 PUREMA H vs. FX80 and 170H ** p< 0.05 30 min vs. 240 min

120 100 80 60 40 20 0

30 min
5527

240 min

Clinical Studies, July 2004 / March 2005

Albumin Removal
3

Albumin in dialysate [g / 4h]

2,5

Polysulfon FX80 Polysulfone FX80, 1.8m PUREMA Purema H H, 1.7m Polyflux170H 170H, 1.7m Polyflux
QB = 300 ml/min QD = 500 ml/min 8 patients

1,5

0,5

5528

Clinical Studies, July 2004 / March 2005

Cystatin C Removal

80

Cystatin C - Removal Ratio [ % ]

70 60 50 40 30 20 10 0

* *

* *

Polysulfon FX80 Polysulfone FX80, 1.8m PUREMA Purema H H, 1.7m Polyflux170 170H, Polyflux H 1.7m
QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 PUREMA H vs. FX80 and 170H

corrected by hematocrit

corrected according to Bergstrm-Wehle

5530

Clinical Studies, July 2004 / March 2005

Cystatin C Clearance

140

**
120

Cystatin C - Clearance [ml/min]

**

Polysulfon FX80 Polysulfone FX80, 1.8m Purema H H, 1.7m PUREMA Polyflux 170 H 1.7m Polyflux 170H,
QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 30 min vs. 240 min ** p< 0.05 vs. FX80 and 170H

100

80

60

40

20

0 30 min
5531

240 min

Clinical Studies, July 2004 / March 2005

Myoglobin Removal
80

Myoglobin - Removal Ratio [%

70 60 50 40 30 20 10 0

Polysulfon FX80 Polysulfone FX80, 1.8m PUREMA Purema H H, 1.7m

QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 vs. FX80

corrected by hematocrit

corrected according to Bergstrm-Wehle

5532

Clinical Study, March 2005

Myoglobin Clearance

80

Polysulfon FX80 Polysulfone FX80, 1.8m

H, 1.7m Purema H PUREMA

Myoglobin - Clearance [ml/ min]

70 60 50 40 30 20 10 0

Polyflux 170H 170H Polyflux

QB = 300 ml/min QD = 500 ml/min 8 patients

30 min
5533

240 min
Clinical Studies, July 2004 / March 2005

PUREMA H Separation Profile

150 125

30 min Clearance [ml/min]

Polysulfon FX FX80, 80 Polysulfone 1.8m Purema H H, 1.7m PUREMA Polyflux 170H Polyflux 170H

100 75 50 25 0 -25 -50 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000

QB = 300 ml/min QD = 500 ml/min 8 patients

Molecular weight [Da]

5534

Clinical Studies, July 2004 / March 2005

PUREMA Biocompatibility: White Blood Cell Count

110 Polysulfon FX80 Polysulfone FX80, 1.8m Polyflux 170H Polyflux 170H, 1.7m Purema H PUREMA H, 1.7m
QB = 300 ml/min QD = 500 ml/min 8 patients

100

90 WBC [ % ]

80

70

60

50 0 30 60 90 120 Time [ min ]

5535

150

180

210

240

Clinical Studies, July 2004 / March 2005

PUREMA Biocompatibility: Complement Activation

7 6 5 C5a [ g/l ] 4 3 2 1 0 0
5536

Polysulfon FX80 Polysulfone FX80, 1.8m Polyflux 170H Polyflux 170H, 1.7m Purema H H, 1.7m PUREMA
QB = 300 ml/min QD = 500 ml/min 8 patients

30

60

90

120 Time [ min ]

150

180

210

240

Clinical Studies, July 2004 / March 2005

PUREMA Biocompatibility: Platelet Count

120 110 100 90 80 70 60 50 0
5537

Polysulfon FX80 Polysulfone FX80, 1.8m Polyflux 170H Polyflux 170H, 1.7m Purema H H, 1.7m PUREMA
QB = 300 ml/min QD = 500 ml/min 8 patients

Platelet Count [ % ]

30

60

90

120 Time [ min ]

150

180

210

240

Clinical Studies, July 2004 / March 2005

PUREMA Biocompatibility: Activation of Coagulation

14 12 10 Polysulfon FX80 Polysulfone FX80, 1.8m Polyflux Polyflux170H 170H, 1.7m Purema H H, 1.7m PUREMA
QB = 300 ml/min QD = 500 ml/min 8 patients

TAT [ g/l ]

8 6 4 2 0 0 30 60 90 120 150 180 210 240

Time [ min ]
5538

Clinical Studies, July 2004 / March 2005

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 significant survival benefit over HD it is common sense that this is due to the superior removal of toxins, in particular middle molecules (low molecular weight proteins) in the first clinical studies, PUREMA proved its outstanding performance the 2m clearance and removal found with PUREMA in HD corresponds to HDF with replacement volumes exceeding 60ml/min with conventional polysulfone membranes

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

orange line represents performance of PUREMA in HD in first clinical trials

5663

Lornoy W et al (2000) Nephrol Dial Transplant, 15 (Suppl. 1): 49-55

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

orange line represents performance of PUREMA in HD in first clinical trials

5663

Lornoy W et al (2000) Nephrol Dial Transplant, 15 (Suppl. 1): 49-55

Clinical study PUREMA H in HD vs. competitors in HDF

Prospective, cross-over design, 8 patients, PUREMA 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, QD=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

250
ns p<0,05 p<0,05 ns ns
H1,7 PUREMA PUREMA H1,7 HD

200 30 min Clearance [ml/min]

Polysulfone PolysulfoneHF80S HF80S HDF, QS= 60ml/min Polyflux Polyflux170H 170H HDF, QS= 60ml/min

150

100

n= 8 corrected for surface area

50

0
5743

Urea

Creatinine

Phosphate

Clinical Study KSPU0603 October 2006

2-Microglobulin Plasma Clearance

100

n.s.
80

n.s.

PUREMA H1,7 PUREMA H1,7 HD Polysulfone Polysulfone HF80S HF80S HDF, QS= 60ml/min Polyflux Polyflux 170H 170H HDF, QS= 60ml/min

2M - Clearance [ml/min]

60

40

n= 8 corrected for surface area

20

HD

HDF
30 min

HDF

HD

HDF
180 min

HDF

Clinical Study KSPU0603 October 2006

2-Microglobulin - Removal Rate

100 90
ns p< 0.05

PUREMA H1,7 PUREMA H1,7 HD Polysulfone HF80S HF80S HDF, QS= 60ml/min

2M - Removal Rate [%]

80 70 60 50 40 30 20 10 0

170H Polyflux 170H HDF, QS= 60ml/min n= 8

HD

HDF

HDF

Removalby Ratio Removal Rate corrected Bergstrm-Wehle

5687

Clinical Study KSPU0603 October 2006

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

100
p< 0.05 p< 0.05 p< 0.05 p< 0.05 p< 0.05
H1,7 PUREMA PUREMA H1,7 HD

2M - Clearance [ml/min]

80

PolysulfoneHF80S HF80S Polysulfone HD, QS= 0ml/min Polyflux170H 170H Polyflux HD, QS= 0ml/min
n= 8 corrected for surface area

60

40

20

HD
0

HD
30 min

HD

HD

HD
180 min

HD

Clinical Study KSPU0603 October 2006

Cystatin C - Removal Rate

80

n.s.

Cystatin C - Removal Rate [%]

70 60 50 40 30 20 10

PUREMA H1,7 PUREMA H1,7 HD Polysulfone Polysulfone HF80S HF80S HDF, QS= 60ml/min Polyflux Polyflux 170H 170H HDF, QS= 60ml/min

n= 8

HD
0

HDF

HDF

RR by BW Removal Rate corrected by Bergstrm-Wehle

5697

Clinical Study KSPU0603 October 2006

Myoglobin - Removal Rate

80

Myoglobin Removal Ratio [%]

p< 0.05

70 60 50 40 30 20 10 0

H1,7 PUREMA H1,7 HD

p< 0.05

Polysulfone HF80S HDF, QS= 60ml/min Polyflux 170H HDF, QS= 60ml/min n= 8

HD

HDF

HDF

Removal Rate corrected by Bergstrm-Wehle RR by BW

5707

Clinical Study KSPU0603 October 2006

Retinol Binding Protein - Removal Rate

70 60
ns

ns

RbP Removal Rate [%]

50 40 30 20 10

PUREMA H1,7 PUREMA H1,7 HD Polysulfone HF80S HF80S Polysulfone HDF, QS= 60ml/min Polyflux 170H 170H Polyflux HDF, QS= 60ml/min

n= 8

HD
0 -10 -20

HDF

HDF

RR by BW Removal Rate corrected by Bergstrm-Wehle

5726

Clinical Study KSPU0603 October 2006

Plasma - 30 min Clearance of Middle Molecules

100

30 m in Clearance [m l/m in]

PUREMA H1,7 PUREMA H1,7 HD

Polysulfone HF80S HF80S HDF, QS= 60ml/min Polyflux 170H 170H HDF, QS= 60ml/min 2m CyC n= 8

75 50 25 0 -25
RbP

Myo

-50
11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000

Molecular weight [Da]

5735

Clinical Study KSPU0603 October 2006

Plasma - 180 min Clearance of Middle Molecules

150

180 min Clearance [ml/min]

125 100 75 50 25 0 -25 -50

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

PUREMA H1,7 PUREMA H1,7 HD Polysulfone HF80S Polysulfone HF80S HDF, QS= 60ml/min Polyflux 170H Polyflux 170H HDF, QS= 60ml/min n= 8 2m CyC

Myo RbP

Molecular weight [Da]

5739

Clinical Study KSPU0603 October 2006

Albumin in Dialysate
2,0
ns ns

PUREMA H1,7 PUREMA H1,7 HD Polysulfone Polysulfone HF80S HF80S HDF, QS= 60ml/min Polyflux Polyflux 170H 170H

Albumin in dalysate [g/4h]

1,5

HDF, QS= 60ml/min n= 8

1,0

0,5

0,0

HD

HDF

HDF

Albumin in dialysate
5709

Clinical Study KSPU0603 October 2006

Summary of PUREMA H Characteristics in Haemodialysis

Improved biocompatibility with significantly lower complement generation Significantly enhanced LMW protein removal Low albumin loss Steeper sieving profile PUREMA in HD provides LMW protein removal comparable to online post-dilution HDF with conventional high-flux membranes

Conclusion

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

Summary of PUREMA 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 Breiter Scientific Marketing Manager, Healthcare Membrana GmbH hder Strasse 28 42289 Wuppertal +49 (202) 6099 786 stefan.breiter@membrana.de