Requested Profiles for Dialysis Membranes Today
Requested Profiles For Dialysis Membranes Today
Prof. Dr. Eng. Jörg Vienken BioSciences, Fresenius Medical Care Bad Homburg Principles of Hemodialysis
Anticoagulation Blood pump
Dialyser, Filter, Artificial Kidney
Routine chronic therapy : 3 treatments / week Duration : ca 4 hrs / treatment Longest therapy in 2008 : 40 years in Japan Guestimate annual cost : ca 50.000,- € / patient Requested Profiles For Dialysis Membranes Today
Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary Dialysis Patients To Date Hemodialysis patients: Annual growth rate 6% 1.300 World population: Annual growth rate 1.1% Annual need for dialysers in 2011: 220,000,000 filters 1.050
900
750 World 2010*: 600 HD: 1,815,000 PD: 213,000 450 Japan 2008** 300 HD: 274,121 PD: 9,300
Patient numbers x 1,000 150 Japan 70,793 HD-Pts >10 years therapy 10,017 HD-Pts >25 years therapy 0 1970 1975 1980 1985 1990 1995 2000 ´05 ´10 Year Re: S Moeller, FMC Annual Survey 2011 ** S. Nakai et al., Ther Apher & Dial, 14:505- 540 (2010) Negative Standards by Opinion Leaders
“Dialysis is useless and dangerous.” Franz Volhard, famous Internist and Professor at Halle (1918) and Frankfurt (1927), both in Germany.
Franz Volhard
“From the initial idea to the actual realization of the dialysis method, it was a very long way. I would have to say, it was the way of the Cross…” Georg Haas(1928) at Giessen, Germany 8022 Bad Homburg, August 1999 2355 Therapy Changes to Come (I)? Incident Age Distribution of Dialysis Patients Germany 1996 - 2002
35 30 25 1996 2002 20 15
Percent10 % 5 0 0-19 20-29 30-39 40-49 50-59 60-69 70-79 > 80 Years 4022 QuaSi-Niere 2002 Therapy Changes to Come (II)? Hemodialysis in the USA
Mean serum creatinin Prevalence by age group at onset of dialysis therapy
Æ Consequences for technical requirements
in dialysis therapy? Re: C Hsu, 8978 J Am Soc Nephrol, 21:1607-1611 (2010) Therapy Changes to Come (III)? Hemodialysis in Japan
Japan 2008
o Mean age of patients: 65,3 years o Mean age of dialysis beginner: 67,2 years o 43,3 % diabetics
o Mean duration of HD therapy: 3.92 hrs
o Average blood flow : 197ml/min o Average dialysate flow: 487 ml/min o 50.7 % with polysulfone membranes o Membrane surface area : 1.63 m² Year 2010
Annual production of capillary membranes for dialysis worldwide: ca.ca. 420.000.000420.000.000 KmKm
ca 3x distance between the Earth and the Sun, or…, ca 10.000 x around equator.
2990 Take Home Message
o Dialysis, the most successful therapy in keeping patients alive e.g., the longest dialysis therapy in Japan: 40 years, 8 months in 2008.
o Dialysis with exponential increase in patient numbers in the years to come: > 6% / annually Æ Need for more filters, tubings and therapies.
o Significant increase of diabetic dialysis patients, Æ Need for adapted therapies essential. Requested Profiles For Dialysis Membranes Today
Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary Membrane - Polymers in Dialysis
End of (Cuprophan) production in 2006
Cellulose-tri-acetate
End of production in 2006
Composite membranes
Composite membranes
4611 Development of Dialyser Sales - World 2000 - 2006 -
180 * Synthetic membrane polymers: Polysulfone, Polyacrylonitrile, PMMA, Polyamide 180 ** Cellulosic membranes: Cuprophan, Hemophan, Cellulose Acetates 160 160
140 140
120 120 Synthetic* high flux membranes ca 50% 100 100
80 80 Synthetic low flux membranes 60 60
Dialysers sold [Mio] 40 Cellulose** high flux membranes 40
20 20 Cellulose low flux membranes 0 0 2000 2001 2002 2003 2004 2005 2006 Year
4865 Re: J Paal, FMC 2008 Take Home Message
o Synthetic membranes – PSu (> 50%), PMMA, PA, PAN, and respective blends, etc - dominate the dialysis market in the world today.
o Reasons for market success and acceptance of synthetic membranes by nephrologists: - versatility - biocompatibility - adsorptive features
o The majority of cellulosic membranes have disappeared from the dialysis market ( exception CTA) after having dominated it in the past decades. Reason: alleged lack of biocompatibility. Requested Profiles For Dialysis Membranes Today
Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary PolymerPolymer selectionselection ofof membranesmembranes
Determinant for the physical (Performance, adsorption) chemical (Biocompatibility) biological-medical (Adverse events, safety) properties of membranes in medical application Current dialysis treatment mainly based on the removal of water and matter!
Capillary- Membrane Fresenius Polysulfone® Filtration, Backfiltration
200 µm 200 µm Inner diameter Pore Sizes of Dialysis Membranes
1,3 nm low flux polysulfone 3,1 nm highflux polysulfone 3,3 nm Helixone (polysulfone)
Cellulosic Membranes Synthetic Membranes
1738-1 Bloodproteins and Their Dimensions
ß-2 Microglobulin Albumin
-charge + charge without charge 4,5 x 2,5 x 2,0 nm
14 x 4 nm
2795-2 p53 Tumor Suppressor Protein
Re: T Chouard Nature, 471:151-153 (2011) Protein Permeability of Dialysis Membranes Analyses of Ultrafiltrate Proteins found in ultrafiltrate SDS-Gel Urine PSu F6: < 0,050 g / L Ultrafiltrate from membrane
Cuprophan: < 0,050 g / L
PSu – F60: 0,069 g / L
Cellulose Acetate: 1,5 g / L
Increasing molecular weight Re: H. Mann, 2007 8149 Interneph Institute, Aachen Proteomics Adding to the complexity of uremic toxins?
Measured polypeptides in filtrate 450 401 400 344 350 307 Highflux F70 300 263 F10 247 250 Lowflux F10 F70 200 182 147 150 137 142 total number total 105 87 100 73 69 50 31 1 17 2 7 0 3 D D D D - - 4 5 k k k k 5 - kD D 1 ,5 2 ,5 , 3 4 k - 1 - 2 2 6 6 8 - 5 - - > 0. 1 1, 2 polypeptide mass class5
1394 Polypeptides in high flux vs 1046 Polypetides in low flux ultrafiltrate samples from uraemic plasma.
EM Weissinger et al., Nephrol Dial Transplant, 19:3068-77 (2004) The Dilemma in Blood Purification Which substances to target ?
EUTox Group: ~ 100 uremic retention solutes EUTox Group: (“Uremic Toxins”) involved. ProteomicsProteomics ¾1300 “toxins” are to be found in the filtrate / urine. people:people: Nephrologists: “We need better membranes and sophisticated Nephrologists: therapies!” Industry: “Tell us which substances should be removed ! Industry: ... and to what extent? Data on concentrations of uremic toxins in human serum vary when analysed in different publications up to a factor of 3!” Is there evidence to support that kidney failure can be attributed to a single substance? Expert Recommendation: Maximise Middle Molecule Removal
Nephrol Dial Transplant, 17(Suppl. 7):16-31 (2002)
How? Æ Use of highflux synthetic membranes Æ Application of convection: Hemodiafiltration HDF Caution! “Opening-up” membrane structure (larger pores) indefinitely would also lead to loss of ‘useful’ proteins (HD = size- exclusion based) Æ Increasing the mean pore size alone is insufficient! High-Flux: Solvent drag Æ Convective Clearance
Convective clearance = SC x QF
Type of f(∆p) membrane:
Low-Flux f(TMP) High-Flux
SC = Sieving Coefficient; QF = Filtrate flow; TMP = Transmembrane pressure 0844-2 Sieving Through Size-Exclusion with Membranes from Polysulfone
Dialysis Therapy of Liver Failure 1 Zone of 0,9 Impermeability 0,8 0,7 0,6 0,5 PSu F6 PSu F60S PSu 0,4 Low flux High Flux AlbuFlow 0,3 Fx60 0,2 Zone of Sievieng coefficient 0,1 Permeability 0 1.000 10.000 100.000 1.000.000 ß2-m Albumin IgG Fibrinogen IgM AlbuFlow PSu – Mol.-Weight Polysulfone
4631-1 Pressure Drop In Dialysers Favours Increased Convection
r ΔL Bloodin • Bloodout QB
η • QB pin pout ΔL Δp = ·(8η· Hagen-Poiseuille´s Law N · r 4 · π QB)
Dialyser Blood
r = Radius of capillary membranes QB = Blood flow L = Dialyser length η = Blood viscosity N = Number of capillary membranes
0845-1 Reduced Internal Fiber Diameter and Higher Clearance of Large Molecules
PSu PSu
PSu – Dialysers: A : 0.5 m² J Vienken & C Ronco Contrib Nephrol, 133: 105-118 (2001) 3850 Ultrafiltration:Ultrafiltration: LowLow-- andand HighfluxHighflux PSuPSu--DialysersDialysers 12000 Highflux Membranes HdF100S Ultrafiltration profiles In vitro, HF 80 (S) human blood,
Hct. 32 %, TP 6 %, QB = 300 ml/min F 70 (S) UF - Ultrafiltration 9000 TMP - Transmembrane pressure F 60 (S)
6000 6000 Lowflux Membranes F 8 HPS
F 7 HPS 4000 F 6 HPS 4000 UF = 3000 ml/h
UF ml/h F 5 HPS
2000 F 4 HPS 2000
0 0 0 100 200 300 400 500 100 200 300 400 500 TMP mmHg 2034-1 FMC, St. Wendel Filtration Profiles Low vs. High-Flux Dialysers
Filtrate flow (QF) & Membrane permeability 12.000 In vitro, Human boodt, Hct.32 %, TP 6 %,
QB = 300 ml/min 10.000 High-Flux
8.000
6.000 Potential 4.000 Gain in Low-Flux Kkonvective 2.000 Ultrafiltration rate [ml/h] Ultrafiltration rate
0 0 100 200 300 400 500 TMP [mmHg]
F4HPS F5HPS F6HPS F7HPS F8HPS F60 F70 HF80 HDF100S
7922 OnLine HDF: the Principle
Reverse Endotoxin Endotoxin osmosis Filter I Filter II
Substitution fluid
Concentrates Dialysis fluid
0140 The dialysis membrane is not a „One-Way-Street“!
0573-1 PSu Fibers: High Intrinsic Adsorptive Features for Endotoxins
Dialysate
Blood
Artificial Organs, 32(9):701–710 (2008)
8100 DC Endotoxinstudies
BC
160 140 120 100 80 60 Intensity 40 20 0 0 10203040506070 PSu µm
Polysulfone capillaries with intrinsic adsorption capacity for ETs.
Re.: M Henry et al., Utah University Artif Organs, 32:701-710 (2008) Reduction of Bacterial Contaminants through Ultrafilters Bacterial concentration Endotoxin - levels CFU/ml IU/ml
100:000 10 10:000 1:000 1 100 10 0.1 1 0.1 0.0 0 0.01 1 0.001 0.001 Standard Post post Standard post post dialysate 1. Filter 2. Filter dialysate 1. Filter 2. Filter EU Standard for ultrapure dialysate. EU Standard for ultrapure dialysate: <0.1 CFU/ml <0.03 IU/ml
C Weber et al., Artif Organs, 24: 323-328 (2000) Water Quality Requirements for Hemodialysis and onLine HDF
Water Concentrates Dialysis fluid OnLine HDF (Ultrapure) Substitution sol.
Ph. Eur 2005 EN 13867 (2002) AAMI 2004 ISO Standard 11663 Ph. Eur 2005 2009
Germ count < 100 < 100 < 0,1 < 10-6 CFU/ml
Endotoxin level < 0.25 <0.5 < 0.03 < 0.01 IU/ml below detection level PolymerPolymer selectionselection ofof membranesmembranes
Determinant for the physical (Performance, adsorption) chemical (Biocompatibility) biological-medical (Adverse events, safety) properties of membranes in medical application CCB Consensus Conference on Biocompatibility Königswinter, Germany, March 1993 Nephrol Dial Transplant, 9(Suppl 2): 1-186 (1994)
Biostability
...... the ability of a substance to remain unchanged in a given biological environment!
0321 Dialyser Sterilisation Procedures European Community 1986 - 2006
1986 1990 12.3% 15% 6% 8.4% 87.7% 70.6%
2006
17% ETO 58% 25% γ - Irradiation Steam Unknown
0244-3 ETO and Anaphylactoid Reactions
ETO (ETO-HSA) bound to Albumin acts as Hapten.
IgE-Antibodies against ETO-HSA provoke allergic reactions in hypersensitive patients.
0250 Ethylene-Oxide Desorptionskinetics of Polymers
200 100 50 Hard PVC 30 LD-PE PA PS PC ABS 10 POM PSu SAN 5 PP 3 HD-PE
ETO ppm 1 EVA PUR Silikone Soft PVC 0 10203040506070 Time days
0255 Handlos 1986 Membrane Polymers and Sterilisation
Membrane- Gamma- ETO Steam Problems Polymer rays Polysulfone + + + Cellulose + + + PVC (hard) + + +
PVC (soft) ++ - Max temperature: 110°C Cell. Acetate ++- Glass-transitiontemp. > 45°C PAN (+?) + - Glass-transitiontemp. > 80°C
PMMA +-(-) ETO - Reservoir, Tmax: 70°C PUR +- + ETO - Reservoir Polyamide ++- Partial: Hydrolysis EVAL ++- Glass-transitiontemp. > 66°C
0245 Ageing of membrane polymers
Æ adverse clinical reactions by extractables The case of Cellulose Acetate
October 1996 Severe loss of hearing and visual troubles in patients of a dialysis center in Alabama/USA Mai 1997 Three patients died Reasons: Use of dialysers with cellulose acetate membranes, manufactured in 1985
Observation: Neurological reactions within 24h after the end of dialysis therapy No reuse
1053 Nephrol News Isues, May 1997; pp 8-13 Dialyser-Extractables and Adverse Clinical Events Changes in Molweight during ageing of CA*-dialysers
* Cellulose acetate
Hutter et al 2640 JAMA, 283:2128-2134 (2000) Adverse Clinical Events Through Extractables from Cellulose Acetate (CA) Dialysers
Symptoms Affected Patients Duration of Occurence after 24 h No % Symptoms
Conjunctivitis 22/22 100 3 - 7 days Ostealgia / Myalgia 21/22 95 1 - 21 days Tinnitus 12/22 55 up to 6 months Headache 4/22 18 3 - 7 days Angiodemias 1/22 4 - Breastache 1/22 4 -
Dialyser: CA 210, Single use NaCl-Rinse + Heparin/NaCl-Rinse Z. Averbukh et al 3810 Artif Organs, 25:437-440 (2001) PolymerPolymer selectionselection ofof membranesmembranes
Determinant for the physical (Performance, adsorption) chemical (Biocompatibility) biological-medical (Adverse events, safety) properties of membranes in medical application Biocompatibility of Membrane Capillaries Contribution of Physical and Biochemical Factors
Commercial Dialysers Membrane Biocompatibility
Blood Coagulation cannot be avoided, if......
Blood stagnant. Blood in contact with air & oxygen interfaces.
Blood in contact with thrombogenic surfaces (collagen, biomaterials). Capillary Lumen Determinant for blood flow and optimized flow behaviour
Impact on normalized platelet density
Blood Flow
Control Aneurysm Norm. Platelet Density
200 μm Stenosis Contraction/expansion
Consequence: Quality requirements for capillary membranes:
Æ Need for homogenous bloodflow paths
2980 Flow Streamlines into Expansion, Contraction and after an Aneurysm
Area of interest CBA
3 2 1 I D •
A 1 2 B 3 Area of interest C II Flow D
Area of interest A B 1 2 C III 3
Schoephoerster et al, 2758 Arterioscler Thromb,13:1806-13 (1993) Domain – Structures of modern Membranes
Polyamide
G. Mishkin Sem Dial, 14:170-173 (2001) Polysulfone / Polyethersulfone
Modified cellulose U. Thomanek Hemophan® Rostock LSM
2885-1 Complement - Activation „Alternative Pathway“
Spontaneous - C3(H O) Bb 2 Terminal C5b C6,C7,C8,C9,C5 complement H I complex (TCC) - 5a Bb C C3 C3b C3b C3b C5
a C3 Membrane surface C3-Convertase
C3b-Binding through nucleophilic Substitutents 0012-1 C5b-9 Complement Activation Levels during Hemodialysis
3000
Unmodified Cellulose
2000 Maximum between 15-60 min
1000 Benzyl-Cellulose C5b-9 ng/ml Cellulose Acetate
Low flux Polysulfone 0 0 30 60 90 120 150 180
Time min N Hoenich et al., 0925-1 Biomaterials, 18:1299-1303 (1997) Blood Pressure Regulation -- after Contact-phase activation -
Endotoxins, neg. charged surfaces Prekallikrein
Factor XIIa HMW Kininogen
Kallikrein Phospholipids
Bradykinin ACE-Inhibitors Prostaglandins Stop X PgE2, Pgl2 ACE (Angiotensin converting enzyme, ACE from lungs and tissue) Blood pressure regulation
0222 Bradykinin Generation in Plasma through negatively - charged surfaces
400 5 min post onset of dialysis 327.6 arterial Mean + SEM n = 10 venous 300
w/o charge + charge-charge w/o charge 200
61.2 91.5 39.7 Normal values 100 18.7 5.1 29.2 17.2 Bradykinin fmol/ml
0 Cuprophan® Hemophan® AN69 Polysulfone GFE 18 GFS Plus 16 Biospal 3000S F60
Verresen et al, 0225 Kidney Int; 45: 1497-1503 (1994) ACE-Inhibitors & Anaphylactoid Reactions Sheepmodel and PAN-Blended Membranes
160
120 80 ** Systolic Blood pressure Pulse 40 AN69 (0) = no ACE-Inhibitors 0 * 160 Pulse 120 * 80 * * * * 40 * Systolic* Bloodpressure AN69 (20) = 20 mg/day Enalapril 0
Pulse beats/min * 160 Pulse 120 80 * 40 * Systolic Bloodpressure mm/hg * * Systolic* Bloodpressure* AN69 (30) = 30 mg/day Enalapril 0 0 5 10 15 20 25 30 35 40 45 50 55 60 time min Membrane: AN69 AN69: PAN – Methallysulfonate- Blend Krieter et al, 1244 Kidney Int, 53: 1026-35 (1998) Bradykinin Generation by PAN Membranes
PAN-ST (surface treated)
A Désormeaux et al., 7763 Biomaterials, 29:1139-1146 (2008) ACE-Inhibitor Arelix September 2003
Warning: Avoid contact of blood with negatively charged surfaces
3815 Take Home Message o Geometry of capillary membranes determines performance and biocomaptibility features. o The membrane is not a one-way street and must be protective against endotoxin passage (through adsorptive features, e.g., based on polysulfone membranes) o Extractables through degradation or after blood leaching important for chronic therapies. o Simultaneously administered medicainl drugs may interfere with polymer structures. o Ethylene oxide as sterilizing agent for membranes and dialysers increasingly replaced by steam sterilization, due to its allergic potential in conjunction with albumin. Requested Profiles For Dialysis Membranes Today
Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary Moiré-Structures and Capillary membranes - Improved Clearance -
Moire Structure
4423 3-D Microwave Structure Analogy with human hair
Hair stuck together once wet, Waved hair separate, and arranged in parallel even if wet Membrane Bundle - Modification for Improved Flow Profiles
A
B A B C
CC
J Vienken & C Ronco 3856 Contrib Nephrol, 133: 105-118 (2001) Homogeneous Dialysateflow through optimized Fiberbundle - Geometry: Improved Diffusive Clearance
Local Urea - Clearance Profile
168 164 158 150 140 168 164 158 150 140
2,4m² in housing 8 2,4m² in housing 8 QB=200ml/min QB=200ml/min QD=500ml/min QD=500ml/min
Conventional Dialyser New FX-Class Lower Need of Dialysis Fluids - Through Moiré-Structured Capillary Membranes -
Reduction
3337 Requested Profiles For Dialysis Membranes Today
Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary Membranes in Dialysis
PropertiesProperties in in needneed System Solutions
Product-Product- PropertiesProperties
19801990 2000 2010 2020?
2254 New Generations of Dialysis Machines - Concept of ”Physiological Dialysis“ -
Sensors
Monitor
Hydraulics
Filter
Dialysis Dialysis Fluid Blood Patient machine Sensors Sensors Sensors OCM® BTM, BVM BPM Protein Functions of Biological Membranes
Leak Gate Pump Carrier Receptor Ca2+ Glucose Na+ Na+ Na+
K+ K+ K+ K+ K+ K+
Na+ Na+ Ca2+ Na+ Glucose
Thicknesses Biological Membranes 10 nm to be compared: Dialysis Membranes 1.000 - 10.000 nm
0169-1