requested profiles for dialysis membranes today€¦ · anticoagulation blood pump principles of...
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Prof. Dr. Eng. Jörg VienkenBioSciences, Fresenius Medical Care
Bad Homburg
Requested Profiles For Dialysis Membranes Today
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Dialyser,Filter, Artificial Kidney
Anticoagulation Bloodpump
Principles of Hemodialysis
Routine chronic therapy : 3 treatments / weekDuration : ca 4 hrs / treatmentLongest therapy in 2008 : 40 years in JapanGuestimate annual cost : ca 50.000,- € / patient
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Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary
Requested Profiles For Dialysis Membranes Today
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Dialysis Patients To Date
Re: S Moeller, FMC Re: S Moeller, FMC AnnualAnnual SurveySurvey 20112011** S. ** S. NakaiNakai et al., et al., TherTher ApherApher & & DialDial, 14:505, 14:505-- 540 (2010)540 (2010)
1970 1975 1980 1985 1990 19950
150
300
450
600
Year
Patie
nt n
umbe
rsx
1,00
0Hemodialysis patients: Annual growth rate 6%World population: Annual growth rate 1.1%
750
900
2000
1.050
´05
World 2010*:World 2010*:HD: 1,815,000HD: 1,815,000PD: 213,000PD: 213,000
Japan 2008**HD: 274,121PD: 9,300
Japan 70,793 HD-Pts >10 years therapy10,017 HD-Pts >25 years therapy
´10
1.300Annual need for dialysers in 2011: 220,000,000 filters
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“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
“Dialysis is useless and dangerous.”Franz Volhard, famous Internist and Professorat Halle (1918) and Frankfurt (1927),both in Germany.
8022
Franz Volhard
Negative Standards by Opinion Leaders
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2355Bad Homburg, August 1999
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Therapy Changes to Come (I)?Incident Age Distribution of Dialysis Patients
Germany 1996 - 2002
4022 QuaSi-Niere 2002
05
1015
20253035
0-19 20-29 30-39 40-49 50-59 60-69 70-79 > 80Years
Perc
ent
% 1996 2002
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8978
Therapy Changes to Come (II)?Hemodialysis in the USA
Re: C Hsu, J Am Soc Nephrol, 21:1607-1611 (2010)
Mean serum creatininat onset of dialysis therapy
Prevalence by age group
Consequences for technical requirementsin dialysis therapy?
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Japan 2008
o Mean age of patients: 65,3 yearso Mean age of dialysis beginner: 67,2 yearso 43,3 % 43,3 % diabeticsdiabetics
o Mean duration of HD therapy: 3.92 hrs
o Average blood flow : 197ml/mino Average dialysate flow: 487 ml/mino 50.7 % with polysulfone membraneso Membrane surface area : 1.63 m²
Therapy Changes to Come (III)?Hemodialysis in Japan
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Year 2010
Annual production of capillary membranesfor dialysis worldwide:
ca. 420.000.000 Kmca. 420.000.000 Km
ca 3x distancebetween the Earth and the Sun, or…, ca 10.000 x around equator.
2990
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Take Home Message
o Dialysis, the most successful therapy in keepingpatients alivee.g., the longest dialysis therapy in Japan:40 years, 8 months in 2008.
o Dialysis with exponential increase in patient numbersin the years to come: > 6% / annually
Need for more filters, tubings and therapies.
o Significant increase of diabetic dialysis patients, Need for adapted therapies essential.
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Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary
Requested Profiles For Dialysis Membranes Today
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Membrane - Polymers in Dialysis
4611
End ofproduction in 2006
End ofproduction in 2006
Cellulose-tri-acetate
(Cuprophan)
Compositemembranes
Composite membranes
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Development of Dialyser Sales- World 2000 - 2006 -
Re: J Paal, FMC 20084865
0
20
40
60
80
100
120
140
160
180
2000 2001 2002 2003 2004 2005 2006Year
Dia
lyse
rsso
ld[M
io]
0
20
40
60
80
100
120
140
160
180
Synthetic* high flux membranes
Synthetic low flux membranes
Cellulose** high flux membranes
Cellulose low flux membranes
ca 50%
* Synthetic membrane polymers: Polysulfone, Polyacrylonitrile, PMMA, Polyamide** Cellulosic membranes: Cuprophan, Hemophan, Cellulose Acetates
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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 ofsynthetic membranes by nephrologists:- versatility- biocompatibility- adsorptive features
o The majority of cellulosic membranes have disappearedfrom the dialysis market ( exception CTA) after havingdominated it in the past decades. Reason: alleged lack of biocompatibility.
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Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary
Requested Profiles For Dialysis Membranes Today
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Determinant for the
physical (Performance, adsorption)chemical (Biocompatibility)biological-medical (Adverse events, safety)
properties of membranes in medicalapplication
Polymer Polymer selectionselection of of membranesmembranes
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200 µm
Capillary-MembraneFresenius Polysulfone®
Inner diameter
Filtration,Backfiltration
200 µm
Current dialysis treatmentmainly based
on the removal of water and matter!
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Pore Sizes of Dialysis Membranes
Cellulosic Membranes Synthetic Membranes
1,3 nm low flux polysulfone3,1 nm highflux polysulfone3,3 nm Helixone (polysulfone)
1738-1
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2795-2
Bloodproteins and Their Dimensions
4,5 x 2,5 x 2,0 nm
- charge
+ charge
without charge
14 x 4 nm
ß-2 Microglobulin Albumin
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Re: T ChouardNature, 471:151-153 (2011)
p53 Tumor Suppressor Protein
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Protein Permeability of Dialysis MembranesAnalyses of Ultrafiltrate
Re: H. Mann, 2007Interneph Institute, Aachen
PSu F6: < 0,050 g / L
Cuprophan: < 0,050 g / L
PSu – F60: 0,069 g / L
Cellulose Acetate: 1,5 g / L
Increasing molecular weight8149
SDS-Gel UrineUltrafiltratefrom membrane
Proteins found in ultrafiltrate
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ProteomicsAdding to the complexity of uremic toxins?
EM Weissinger et al.,Nephrol Dial Transplant, 19:3068-77 (2004)
1394 Polypeptides in high flux vs
1046 Polypetides in low flux ultrafiltrate samplesfrom uraemic plasma.
Measured polypeptides in filtrate
73
307263
182137
87
311 2
105
401
344
247
147 142
6917 7
050
100150200250300350400450
0.8 - 1 kD
1 - 1,5 kD
1,5 - 2 kD
2 - 2,5 kD 2,5 - 3 3 - 4
4 - 5
5 - 6 kD> 6 kD
polypeptide mass class
tota
l num
ber
F10F70
Highflux F70
Lowflux F10
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Is there evidence to support that kidney failurecan be attributed to a single substance?
The Dilemma in Blood PurificationWhich substances to target ?
“Tell us which substances should be removed !... 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!”
Industry:Industry:
“We need better membranes and sophisticated therapies!”Nephrologists:Nephrologists:
1300 “toxins” are to be found in thefiltrate / urine.
Proteomics Proteomics people:people:
~ 100 uremic retention solutes(“Uremic Toxins”) involved.EUToxEUTox Group:Group:
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Expert Recommendation:Maximise Middle Molecule Removal
How? Use of highflux synthetic membranesApplication of convection: Hemodiafiltration
HDFCaution! “Opening-up” membrane structure (larger pores) indefinitely
would also lead to loss of ‘useful’ proteins (HD = size-exclusion based)
Increasing the mean pore size alone is insufficient!
Nephrol Dial Transplant, 17(Suppl. 7):16-31 (2002)
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SC = Sieving Coefficient; QF = Filtrate flow; TMP = Transmembrane pressure0844-2
High-Flux:Solvent drag Convective Clearance
f(∆p)
f(TMP)
Type of membrane:
Low-Flux
High-Flux
Convective clearance = SC x QF
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Sieving Through Size-Exclusion with Membranesfrom Polysulfone
00,10,20,30,40,50,60,70,80,9
1
1.000 10.000 100.000 1.000.000
Mol.-Weightß2-m Albumin IgG Fibrinogen IgM
Siev
ieng
coef
ficie
nt
PSuPSu F6F6Low Low fluxflux
DialysisDialysisZone of
Impermeability
Zone ofPermeability
4631-1
AlbuFlowPSu –
Polysulfone
PSu F60SPSu F60SHigh High FluxFlux
Fx60Fx60
PSuPSuAlbuFlowAlbuFlow
TherapyTherapy of of LiverLiver FailureFailure
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0845-1
Pressure Drop In DialysersFavours Increased Convection
Bloodin Bloodout QB
ΔL
Δp = ΔL
N · r r 4 · π
r
pin pout
•
Hagen-Poiseuille´s Law· (8η·QB)
η • QB
Dialyserr = Radius of capillary membranesL = Dialyser lengthN = Number of capillary membranes
BloodQB = Blood flowη = Blood viscosity
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J Vienken & C RoncoContrib Nephrol, 133: 105-118 (2001)
Reduced Internal Fiber Diameter and HigherClearance of Large Molecules
PSu PSu
PSu – Dialysers: A : 0.5 m²
3850
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2034-1
Ultrafiltration:Ultrafiltration: LowLow-- and and HighfluxHighflux PSuPSu--DialysersDialysers
FMC, St. Wendel
Ultrafiltration Ultrafiltration profilesprofilesIn vitro, human blood,Hct. 32 %, TP 6 %, QB = 300 ml/min
UF - UltrafiltrationUltrafiltrationTMP - TransmembraneTransmembrane pressurepressure
0
TMP mmHg
0
2000
4000
6000
0 100 200 300 400 500
F 8 HPS
F 7 HPSF 7 HPSF 6 HPS
F 5 HPS
F 4 HPS
UF
ml/h
UF = 3000 ml/h
Lowflux Membranes6000
4000
2000
100 200 300 400 500
HF 80 (S) HF 80 (S)
F 70 (S) F 70 (S)
F 60 (S) F 60 (S) 9000
12000HdF100S HdF100S Highflux Membranes
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Filtration ProfilesLow vs. High-Flux Dialysers
In vitro, Human boodt,Hct.32 %, TP 6 %,QB = 300 ml/min
Ultr
afilt
ratio
n ra
te [m
l/h]
TMP [mmHg]
High-Flux
Low-FluxPotential Gain in Kkonvective
Filtrate flow (QF) & Membrane permeability
0
2.000
4.000
6.000
8.000
10.000
12.000
0 100 200 300 400 500
F4HPS F5HPS F6HPS F7HPS F8HPS F60 F70 HF80 HDF100S
7922
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0140
OnLine HDF: the Principle
Reverseosmosis
EndotoxinFilter I
EndotoxinFilter II
Dialysis fluid
Concentrates
Substitution fluid
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0573-1
The dialysis membrane is nota „One-Way-Street“!
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PSu Fibers:High Intrinsic Adsorptive Features for Endotoxins
Artificial Organs, 32(9):701–710 (2008)
Blood
Dialysate
8100
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Endotoxinstudies
Re.: M Henry et al., Utah UniversityArtif Organs, 32:701-710 (2008)
0
2040
6080
100
120140
160
0 10 20 30 40 50 60 70µm
Inte
nsity
PSu
Polysulfone capillaries with intrinsic adsorption capacity for ETs.
BC
DC
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C Weber et al., Artif Organs, 24: 323-328 (2000)
0
Standarddialysate
Post1. Filter
post2. Filter
Bacterial concentrationCFU/ml
EU SEU Standardtandard for for ultrapure ultrapure dialysatedialysate..<0.1 <0.1 CFU/mlCFU/ml
0.001
0.1
10:0001:000
100:000
0.01
10100
1
Reduction of Bacterial Contaminantsthrough Ultrafilters
EU Standard for ultrapure EU Standard for ultrapure dialysatedialysate: : <0.03 <0.03 IU/mlIU/ml
0.01
0.001Standarddialysate
post1. Filter
Endotoxin - levelsIU/ml
1
0.1
10
post2. Filter
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Water Quality Requirementsfor Hemodialysis and onLine HDF
Water Concentrates Dialysis fluid OnLineOnLine HDFHDF(Ultrapure) Substitution sol.
Germ count < 100 < 100 < 0,1 < 10-6
CFU/ml
Endotoxin level < 0.25 <0.5 < 0.03 < 0.01IU/ml below detection
level
Ph. Eur 2005 EN 13867 (2002) AAMI 2004 ISO Standard 11663Ph. Eur 2005 2009
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Determinant for the
physical (Performance, adsorption)chemical (Biocompatibility)biological-medical (Adverse events, safety)
properties of membranes in medicalapplication
Polymer Polymer selectionselection of of membranesmembranes
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0321
Biostability
.......the ability of a substance toremain unchanged in a given
biological environment!
CCBConsensus Conference on Biocompatibility
Königswinter, Germany, March 1993Nephrol Dial Transplant, 9(Suppl 2): 1-186 (1994)
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0244-3
Dialyser Sterilisation ProceduresEuropean Community 1986 - 2006
1986 1990
ETOγ
SteamUnknown
- Irradiation
87.7%
12.3%
70.6%
15% 6%8.4%
25%58%17%
2006
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0250
ETO and Anaphylactoid Reactions
ETO (ETO-HSA) bound to Albumin acts as Hapten.
IgE-Antibodies against ETO-HSAprovoke allergic reactions in hypersensitive patients.
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Handlos 1986
Time days
ETO
pp
m
0 10 20 30 40 50 60 70
1
35
10
3050
100200
PSPC ABS POM PSu SAN
LD-PE
PP
EVAPUR SilikoneSoft PVC
Hard PVC
HD-PE
PA
Ethylene-OxideDesorptionskinetics of Polymers
0255
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0245
Membrane Polymers and Sterilisation
Gamma-rays
ETO Steam
Cell. AcetatePANPMMA
PolyamideEVAL
Glass-transitiontemp. > 45°CGlass-transitiontemp. > 80°CETO - Reservoir, Tmax: 70°C
Partial: HydrolysisGlass-transitiontemp. > 66°C
+ + -(+?) + -
+ - (-)
+ + -+ + -
PolysulfoneCellulosePVC (hard)
+++
Membrane-Polymer
Problems
PVC (soft) Max temperature: 110°C+ + -
PUR ETO - Reservoir+ - +
+++
+++
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1053
Ageing of membrane polymers
adverse clinical reactions by extractablesThe case of Cellulose Acetate
October 1996 Severe loss of hearing and visualtroubles in patients of a dialysiscenter in Alabama/USA
Mai 1997 Three patients diedReasons: Use of dialysers withcellulose acetate membranes, manufactured in 1985
Observation:Observation: Neurological reactions within 24h after the end of dialysis therapyNo reuse
Nephrol News Isues, May 1997; pp 8-13
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Hutter et alJAMA, 283:2128-2134 (2000)
Dialyser-Extractables and Adverse Clinical EventsChanges in Molweight during ageing of CA*-dialysers
2640
* Celluloseacetate
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Adverse Clinical Events Through Extractablesfrom Cellulose Acetate (CA) Dialysers
Z. Averbukh et alArtif Organs, 25:437-440 (2001)
Symptoms Affected Patients Duration ofOccurence after 24 h No % Symptoms
Conjunctivitis 22/22 100 3 - 7 daysOstealgia / Myalgia 21/22 95 1 - 21 daysTinnitus 12/22 55 up to 6 monthsHeadache 4/22 18 3 - 7 daysAngiodemias 1/22 4 -Breastache 1/22 4 -
Dialyser: CA 210, Single useNaCl-Rinse + Heparin/NaCl-Rinse
3810
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Determinant for the
physical (Performance, adsorption)chemical (Biocompatibility)biological-medical (Adverse events, safety)
properties of membranes in medicalapplication
Polymer Polymer selectionselection of of membranesmembranes
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Contribution of Physical and Biochemical FactorsBiocompatibility of Membrane Capillaries
Commercial Dialysers
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Blood Coagulation cannot be avoided, if.........
Blood stagnant.
Blood in contact with air & oxygen interfaces.
Blood in contact with thrombogenicsurfaces (collagen, biomaterials).
Membrane Biocompatibility
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200 μm
Capillary LumenDeterminant for blood flow and optimized flow behaviour
Consequence: Quality requirements for capillary membranes:
Need for homogenous bloodflow paths
2980
Nor
m. P
late
letD
ensi
ty
Blood Flow
Aneurysm
Stenosis Contraction/expansion
Control
Impact on normalized platelet density
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AC B
D
2758
Area of interest
Area of interest
Area of interest
A
A
B
BC
C
D
123
3
12
3 2 1I
II
III
Schoephoerster et al,Arterioscler Thromb,13:1806-13 (1993)
Flow Streamlines into Expansion, Contractionand after an Aneurysm
Flow
•
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2885-1
Modified celluloseHemophan®LSM
U. ThomanekRostock
G. MishkinSem Dial, 14:170-173 (2001)
Domain – Structures of modern Membranes
Polyamide
Polysulfone / Polyethersulfone
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0012-1
Complement - Activation„Alternative Pathway“
Membrane surface
C6,C7,C8,C9,C5Terminal complementcomplex(TCC)
C3b C3b C3b
H I
SpontaneousC3(H2O)
-Bb
C5a
C5
C5b
C3a
Bb-
C3
C3C3--ConvertaseConvertase
C3b-Binding through nucleophilic Substitutents
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0925-1
C5b-9 Complement ActivationLevels during Hemodialysis
N Hoenich et al.,Biomaterials, 18:1299-1303 (1997)
0
1000
2000
3000
0 30 60 90 120 150 180
Time min
C5b
-9
ng/m
l
Unmodified Cellulose
Cellulose Acetate
Low flux Polysulfone
Benzyl-Cellulose
Maximum between15-60 min
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0222
Blood Pressure Regulation-- after Contact-phase activation -
Endotoxins,neg. charged
surfacesPrekallikrein
Kallikrein
HMW KininogenFactor XIIa
Phospholipids
Blood pressure regulation
ProstaglandinsPgE2, Pgl2
(Angiotensin converting enzyme, ACE from lungs and tissue)
ACE
ACE-InhibitorsStopX
Bradykinin
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0225
Bradykinin Generation in Plasma through negatively - charged surfaces
Cuprophan®GFE 18
Hemophan®GFS Plus 16
AN69Biospal 3000S
PolysulfoneF60
0
100
200
300
400
Bra
dyki
nin
fmol
/ml
arterialvenous
5 min post onset of dialysisMean + SEMn = 10
18.7 5.1 29.2 17.2
61.2 91.5 39.7
327.6
Verresen et al,Kidney Int; 45: 1497-1503 (1994)
Normal values
w/o charge + charge w/o charge- charge
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1244Krieter et al,
Kidney Int, 53: 1026-35 (1998)
ACE-Inhibitors & Anaphylactoid ReactionsSheepmodel and PAN-Blended Membranes
Membrane: AN69 AN69: PAN – Methallysulfonate- Blend
0
40
80
120
160
0
40
80
120
160
0 5 10 15 20 25 30 35 40 45 50 55 60
0
40
80
120
160
* *
*
*
* * * * * *
*
* * * * * *Syst
olic
Blo
odpr
essu
rem
m/h
gPu
lse
bea
ts/m
in
time min
Systolic Blood pressure PulseAN69 (0) = no ACE-Inhibitors
AN69 (20) = 20 mg/day Enalapril
AN69 (30) = 30 mg/day Enalapril
Systolic Bloodpressure
Systolic Bloodpressure
Pulse
Pulse
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A Désormeaux et al.,Biomaterials, 29:1139-1146 (2008)
Bradykinin Generation by PAN Membranes
7763
PAN-ST(surface treated)
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ACE-Inhibitor Arelix September 2003
3815
Warning: Avoid contact of blood with negatively charged
surfaces
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Take Home Message
o Geometry of capillary membranes determinesperformance and biocomaptibility features.
o The membrane is not a one-way street and must beprotective against endotoxin passage (through adsorptivefeatures, e.g., based on polysulfone membranes)
o Extractables through degradation or after blood leachingimportant for chronic therapies.
o Simultaneously administered medicainl drugs mayinterfere 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.
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Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary
Requested Profiles For Dialysis Membranes Today
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4423
MoireStructure
Moiré-Structures and Capillary membranes- Improved Clearance -
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3-D Microwave StructureAnalogy with human hair
Waved hair separate, even if wet
Hair stuck together once wet, and arranged in parallel
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Membrane Bundle - Modificationfor Improved Flow Profiles
J Vienken & C RoncoContrib Nephrol, 133: 105-118 (2001)3856
A B C
A
B
CC
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168 164 158 150 140 168 164 158 150 140
2,4m² in housing 8QB=200ml/minQD=500ml/min
2,4m² in housing 8QB=200ml/minQD=500ml/min
Local Urea - Clearance Profile
Conventional Dialyser New FX-Class
Homogeneous Dialysateflow through optimizedFiberbundle - Geometry:
Improved Diffusive Clearance
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Lower Need of Dialysis Fluids- Through Moiré-Structured Capillary Membranes -
3337
Reduction
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Membrane polymers
Performance and Biocompatibility
Conditions for Dialyser Choices
Summary
Requested Profiles For Dialysis Membranes Today
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Membranes in Dialysis
1980 201020001990
Properties in need
Properties in need
Product-PropertiesProduct-
Properties
System System SolutionsSolutions
2254
2020?
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New Generations of Dialysis Machines- Concept of ”Physiological Dialysis“ -
Dialysis machine
Dialysis FluidSensors
BloodSensors
PatientSensors
SensorsSensors
HydraulicsHydraulics
BTM, BVM BPMOCM®
Filter
MonitorMonitor
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Na+
K+ K+K+
Na+ Na+Na+
Na+ Na+
K+K+ K+
K+
Leak Gate Pump Carrier ReceptorCa2+
Glucose
Protein Functions of Biological Membranes
0169-1
Ca2+
Glucose
Thicknesses Biological Membranes 10 nmto be compared: Dialysis Membranes 1.000 - 10.000 nm