Mebranes sterilflux hani hafez may2017

Membranes,
Sterilization,
and Flux
MOHAMED HANI HAFEZ
Professor of Medicine &Nephrology-cairo University

 45 % - 23% OBESITY
 27%
HYPERTENSION
 8% - 7% DIABETES
MELLITUS
Who report 2012
CAUSES OF DEATH IN
EGYPT
CARDIOVASCULAR
TUMORS
RESPIRATORY
DM
OTHER

Concerns in CKD-5 management in Egypt
 Late referral
 Inadequate Control of the 2 major risk factors(HTN 32%-DM
18%)
 High Flux/HDF limited
 Quality of life and decrease co-morbidity : CKDMBD ,CVD
 Anemia control and still Burden of Hepatitis C
 Pricing of dialysis sessions (650 dialysis centers :70% public -
30%private) MoH (Ministry of Health) Hospitals.-University,
Military & Police) Hospitals
 PD (<1%) total HD patients 50569 in 2014(with 10% yearly
increase)

Transplant Regulation and law implementation
 High Committee of Organ Tx:
Licensing and Re-license
Brain death
Training ICU doctors, teams andCoordinators(Cairo and Mansoura )
Auditing and Supervision
Medical protocols
Mortality &Morbidity data collection
 Statistics Problem? Multiple sources for patient
registry in Egypt ESNT(1978),ESOT(2013)- Ministry of Health “High
Committee of Organ tx”-University records)

15.4
5.8
3.5
2.6
1.41.51.2
2.2
4.1
6.2
8.1
5.7
7.6
3.8
6.3
3.8
3
2.5
3.4
1.6
3.2
1.7
0.4
0.2
0.40.40.2
3.8
0
2
4
6
8
10
12
14
16
18
‫القاهرة‬
‫الجيزة‬
‫القليوبية‬
‫الفيوم‬
‫بورسعيد‬
‫االسماعيلية‬
‫السويس‬
‫دمياط‬
‫الشيخ‬‫كفر‬
‫االسكندرية‬
‫البحيرة‬
‫الغربية‬
‫الدقهلية‬
‫المنوفية‬
‫الشرقية‬
‫المنيا‬
‫سويف‬‫بنى‬
‫قنا‬
‫سوهاج‬
‫االقصر‬
‫اسيوط‬
‫اسوان‬
‫مطروح‬‫مرسى‬
‫الجديد‬‫الوادى‬
‫االحمر‬‫البحر‬
‫سيناء‬‫شمال‬
‫سيناء‬‫جنوب‬
‫الجيش‬

‫توزيع‬‫اطباء‬‫المحافظات‬ ‫على‬ ‫الكلوى‬ ‫الغسيل‬DISTRIBUTION OF STAFF

Etiology of chronic kidney disease in HD
patients in Egypt (n=22,070)
Sarhan I, et al. Ain Shams University, 2014
PKD, polycystic kidney disease
Percentage
0
5
10
15
20
25
30
35
40

Membranes
• Types
• Reaction
• Classification of filters
1)Membranes

• Cellulose, also called cuprophan (or cuprophane), is a polysaccharide-
based membrane obtained from pressed cotton. It is composed of chains
of glucosan rings with abundant free hydroxyl groups.
• Substituted cellulose membranes are obtained by chemical bonding of a
material to the free hydroxyl groups at the surface of the cellulose
polymer. The most common type is cellulose acetate, in which acetate
replaces 80 percent of the hydroxyl groups.
• Cellulosynthetic membranes are modified by the addition of a synthetic
material (such as diethylaminoethyl in the production of Hemophane®) to
liquefied cellulose during its formation.
• Synthetic noncellulose membranes which have a higher permeability and
are more biocompatible (and more expensive) than the cellulose
membranes. There are a variety of synthetic membranes available,
including polyacrylonitrile (PAN), acrylonitrile-sodium methallyl sulfonate
(AN-69), polysulfone, polycarbonate, polyamide, and
polymethylmethacrylate (PMMA) membranes
TYPES OF HEMODIALYSIS MEMBRANES

TYPES OF HEMODIALYSIS MEMBRANES
Cellulose
• primarily manufactured as cuprophan ,is a
polysaccharide-based membrane obtained from
pressed cotton.
• It is composed of chains of glucosan rings with
abundant free hydroxyl groups.
• Cupammonium is primarily used in the
manufacturing process of this membrane (hence
the name), but other methods of manufacturing
exist.
• These membranes, which are generally low flux,
are best considered to be bioincompatible

Substituted cellulose and Cellulosynthetic
• obtained by chemical bonding or substitution of a material
to the free hydroxyl groups at the surface of the cellulose
polymer.
• The most common type is cellulose acetate in which acetate
replaces 80 percent of the hydroxyl groups.
• Such membranes can also be modified by the addition of a
synthetic material (such as diethylaminoethyl in the
production of Hemophane®) to liquefied cellulose during its
formation.
• This class of membranes has a broad range of
biocompatibility, ranging from relatively bioincompatible (as
with cellulose acetate) to biocompatible (as with cellulose
triacetate).
• The permeabilities of these membranes range from high to
low flux.

Synthetic noncellulose
• have a higher permeability and are more
biocompatible than the cellulose membranes.
• There are a variety available including
polyacrylonitrile (PAN), polysulfone,
polycarbonate, polyamide, and
polymethylmethacrylate (PMMA) membranes.
• They have permeabilities that range from low
to high flux.

Determinants of biocompatibility
• The free hydroxyl groups on the cellulosic dialysis membrane
activate the alternate pathway of complement, leading to
neutrophil activation and subsequent sequestration in the
pulmonary circulation and infiltration in other organs
• There are several sequelae of complement activation:
Release of anaphylatoxins (C3a and C5a)-Formation of the
membrane attack complex (C5b-9)-Activation of neutrophils and
monocytes
• The side group modifications on substituted cellulose membranes
and the high adsorptive capacity of synthetic membranes
generally lead to a decrease in the intensity of blood membrane
interactions.
• As an example, the PAN membrane can vigorously activate the
complement system; however, it also has a high adsorptive
capacity for complement, resulting in a low net level of
complement activation products reaching the systemic circulation

• The coagulation cascade is activated rapidly by surfaces of
all membranes. During hemodialysis, this cascade is
purposely blunted by heparin
• Neutrophils, monocytes, lymphocytes, red cells, and
platelets are all activated by contact with the
hemodialysis membrane resulting in upregulation of
adhesion receptors, release of proteinases and other
intracellular enzymes, reactive oxygen species,
leukotrienes, platelet activating factor, interleukin-1 (IL-1),
tumor necrosis factor and to release of thromboxanes.
These factors may be important determinants of the
consequences of bioincompatibility.

• Hemodialysis with cuprophane membranes (but
not more compatible membranes) may lead to
neutrophilic infiltration into the kidney (and other
tissues) and delayed recovery from acute renal
failure.
• Some studies suggest that the use of
biocompatible membranes is associated with a
lower morbidity and mortality.
• As a result of these data, nephrologists in the
United States have increased the use of modified
cellulose or synthetic membranes

biocompatibility of the membrane may
influence :
• the accumulation of beta-2 microglobulin,
• nutritional status
• susceptibility to infection
• the loss of residual renal function

Dialyzer reactions
• refer to all of the abnormal sequelae resulting
from the interaction between blood
constituents and the hemodialysis membrane.
• There are two types of reactions: type A and
type B.
• Type A is far less common but more severe
than type B

Type A reactions
• usually begin in the first few minutes of dialysis although
the onset may be delayed for up to 30 minutes.
• Mild symptoms include itching, burning sensation at the
access site, urticaria, flushing, cough, sneezing, wheezing,
abdominal cramps, diarrhea, headache, back and chest
pain, nausea, vomiting, fever, and chills.
• More severe reactions lead to dyspnea, a sense of
impending doom, and hypotension, potentially resulting
in cardiac arrest and death.
• Type A reactions are probably caused by leachable
substances from the dialyzer (such as ethylene oxide) or
by contamination with bacterial peptides

Type A reactions prevention &ttt
• Can usually be prevented by proper rinsing of the dialyzer,
adequate sterilization techniques for the dialysis machine,
(reuse of the dialyzer), Avoiding PAN membranes in
patients treated with an ACE inhibitor. Sterilization of the
dialyzer with gamma irradiation or steam
• pretreatment with antihistamines and/or steroids may be
necessary during the first use in patients with a previous
history of a type A reaction
• treatment of a type A reaction is stopping dialysis
immediately without returning the blood to the patient.
Other therapies that may be used include antihistamines,
steroids, epinephrine, bronchodilators, and/or pressors

Type B reactions
• occur in 3 to 5 percent of patients dialyzed with
new cellulosic membranes and are mediated by
complement. The most common symptoms are
chest and back pain, dyspnea, nausea, vomiting,
and hypotension.
• Anaphylaxis is extremely rare.
• In contrast to type A reactions, type B symptoms
typically do not occur until 15 to 30 minutes into
the dialysis treatment
• there is generally an improvement in symptoms
with continuation of the dialysis treatment

• Differential diagnosis of type B reactions include
other acute complications of dialysis such as
hemolysis, air embolism, dialysis-associated
episodic hypotension, dialysis-induced
hypoxemia and dialysis dysequilibrium.
• The treatment of type B reactions is typically
supportive, since the symptoms
characteristically resolve as dialysis is continued
Type B reactions

Evaluation Points of Hollow Fibers Dialyzers
(Suggestd TOTAL MARK OUT OF 26)
• A-Manufacturing: Polymer
• B-Performance
• C-Sterilization
• D-Biocompatibility
• E-Endotoxin Retention Capacity

A-Manufacturing
:
-Choice of Polymer material from superior to inferior:
1-Helixone Plus
2-Helixone
3-Polysulphone
4-Polyamide
5- Polyethersulphone
-High Tech Fiber Production from superior to inferior according to production
capacity:
1-Mass production Capacity
2-Middle Production Capacity
3-Low production Capacity
-Membrane Structure(Sponge Like Structure) which support excellent performance
& high Safety
-Uniform Potting material(Polyurethan)and smooth cutting(Affect performance)
-smooth pores .
-Microundulation(regular distribution of dialysate around fibers)

2- Performance
-Clearance
Uremic Toxins should be removed
*small( less than 500 Dalton) like Urea
*Middle(up to 12000 Dalton) Like B2M
* large (More than 12000) Like Leptin, Myoglobin
-Pore Size(Low Flux, High Flux)
-Ultrafilteration Coefficient
-Sieving Coefficient(Low Flux, High Flux)
B2M Sieving Coefficient should be toward 1 (Solute can pass)
Helixone Plus(FX Cordiax) S co of B2M is 0.9(Means 90% Clearance)
Helixone(FX Classix) S co of B2M is 0.7 (Means 70% Clearance)
-Albumin Loss
* depending on production technology of membrane material.
*Nanocontrolled Spinning Technology as new technique may decrease
loss of albumin

FILTER MEMBRANE SPECIFICATIONS
natural function of the kidney with the normal sieving
coefficient.

3-Sterilization
Sterilization ranked from superior to inferior:
1-Inline Steam Sterilization(no disadvantages).
2-Steam Sterilization
3- Gamma Radiation

4-Biocompatability
-low Complement Activation
-low Leukocyte Activation & inflammatory
mediators.
-No Anaphylactic Reaction
-Low Membrane Thrombogenicity( platelet
activation)
-Low anticoagulation dose

5- Endotoxin Retention Capacity
-Endotoxin are the lipopolysaccharide from outer membrane of Gram
Negative Bacteria.
-They can be chemically broken into smaller fragment which can pass
membrane.
-They can cause acute or chronic reaction
-They come from dialysate or water system
-Membrane should have high Endotoxin retention capacity providing
safety to patient blood( As in Helixone& Polysulphone).
-Endotoxin Retention capacity depend on membrane manufacturing
and structure.
-Membranes raking from superior to inferior:
1-Helixone Plus
2-Helixone
3-Polysulphone
4-Polyamide
5-Polythersulphone

STERILIZATION
• Spreading Infections
• Medical Products Sterilization
From history to innovation
• Dialysis Products Sterilization
2)Sterilization

CHANGING FACIES of Infections
• TB Again
• Old STDs now HIV
• SARS
• HEPATITIS
• H1N1
• EBOLA
• ZIKA
• What else ?????

Global Distribution of HCV Varies by Genotype
genotype 4 13% (4th in %)
(but in Egypt 93%)
31
31
Negro F and Alberti A. The global health burden of hepatitis C virus infection. Liver International. 2011:31 (Suppl 2); pp 1-3
O'Leary JG, Davis GL. Hepatitis C. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease:
Pathophysiology/Diagnosis/Management. 9th ed. Philadelphia, PA: Saunders, Elsevier Inc.; 2010:1313-1335.
Dienstag JL. Acute Viral Hepatitis. In: Longo Gastroenterology. … 349-377.
Kamal and Nassar. Hepatitis C Genotype 4: What We Know and What We Don’t Yet Know. Hepatology. 2008:47:1371-1383.
31
Genotypes
1 ( 83.4m )-3 ( 54.3m )
2( 16.5m )-4( 15 m )
6 (9,8 m) -5( 7.4m ) smith et al hepat 2014
~170 Million Chronic HCV
(2.3%of world population)

Relationship Between HCV and CKD
Persons with kidney disease
are at an increased risk of
acquiring HCV from exposure
to HCV-contaminated blood
during transfusions or medical
equipment during dialysis or
transplant
Kidney Disease: Improving Global Outcomes. Kidney Int. 2008;73(Suppl 109):S1-S99.
Fissell RB, Bragg-Gresham JL, Woods JD, et al. Kidney Int. 2004;65:2335-2342.
7.3%
9.4%
13.3% 14.2%
22.5%
29.4%
38.9%
51.0%
58.3%
0
10
20
30
40
50
60
70
<0.25 <3 3-5 6-8 9-11 12-14 15-17 18-20 >23
HCVprevalence,%
Years on hemodialysis
EGYPT Dialysis10-90%
Mahmoud et al,BMC
Infectious diseases13::288,2013
Ain SHAMS: around 50%--conversion 20%

Relationship Between HCV and CKDPersons with kidney disease are at an
increased risk of acquiring HCV from exposure to HCV-contaminated blood
during transfusions or medical equipment during dialysis
HCV
Free
49.1%
Current
HCV+ve
50.90%
0% 0%
.
EGYPT
1-Dialysis10-90%
Mahmoud et al,BMCInfectious diseases13::288,2013
(Mansoura Group and Ain ShamsGroup)
2-Serconversion rate (world 1.38-1.9per y)
AntiHCV prevalence 50.9(or50.9)
22070 studied
13646 were free at start(62%) cumulative
conversion of 20.4%
Ain Shams group
3-Relative Risk for HCV seroconversion riskFactors (RR)
SeroCONVERSION rate 6%per year
Blood transfusion 2.68
Shistosomiasis 1.7
Surgery 1.5
Switching of Hemodialysis 1.5
Longer dialysis,Age<familyHistory of HepC(Mansoura Group)

N of patients seroconverted in
Different governorates

SEPSIS BIG KILLER IN ICUs
• NOSOCOMIAL INFECTIONS
• BAD PROGNOSIS OF SEPTIC PATIENTS
• ANTIBIOTIC RESISTANCE

• Looked at 130,781 patients in 2746 facilities in Japan at end of 2006
• Examined facility level dialysis fluid endotoxin levels
• Rate of all-cause mortality was linked to endotoxin levels
– 1 year mortality was highest in the >0.1 EU/mL (88 deaths per 1000 person-years)
– This group had increased risk of all cause mortality of 28% (95% CI 10−48) compared with the
<0.001 EU/mL group
• Need to consider this modifiable risk factor – how?
• Increasing efficiency of water treatment unit and audit
– Extra Reverse Osmosis membrane
– Regular replacement of filters
– Technology may assist with
Adding more bacterial filters
Adding endotoxin filter in each HD
machine to be replaced each
(100 sessions)
for delivery of ultrapure dialysate
Hasegawa T, et al. Am J Kidney Disease 2015 Jan 29; Epub
Importance of ensuring HD water quality

MP674] EDTA,2014EPIDEMIOLOGY OF INFECTIONS REQUIRING HOSPITALISATION DURING
LONG TERM FOLLOW UP IN KIDNEY TRANSPLANT PATIENTS.
Laure Champion1, Christel Renoux2, Christine Randoux3, Caroline Du Halgouet3, Latifa Azeroual3, Denis
Glotz4, Francois Vrtovsnik3, Eric Daugas3
1Hopital Bichat, Paris, France2Mc Gill University, Montreal, QC, Canada3Hopital Bichat, Paris,
France4Hopital Saint Louis, Paris, France
[.
METHODS: We performed a retrospective cohort study of 314 consecutive renal
transplant recipients from 1999 to 2012. We stratified the cohort in three periods according to
the date of renal transplantation (P1:1999-2003: n=61; P2:2004-2007: n=89; P3:2008-2012: n=164).
RESULTS: The patients who underwent a transplant during P3 were older, had more cardiovascular
risks factors, higher title of pre-transplant antibodies, and received an antithymocyte globulin
induction therapy more often. At 3 and 5 years, the graft and patient survival rates were 95%-89%
and 95%-89% respectively, with an increased incidence of acute rejection from P1 to P3 (1.69; 5. 62;
6. 83). Overall, 172 (54. 8%) patients developed at least one serious infection in a total of 381 IRH
during a median follow-up of 4.18 years. The median time to the occurrence of the first IRH was
shorter for most recent transplant recipients: P1 : 9.53 years (IC-95% : 3.40 to non estimable) ; P2 :
2.83 years (1.30-4.55) ; P3 : 1,74 years (0.95-3.88) (p<0.05). Incidence rate of IRH adjusted for sex
and age (3.38; 9.1; 14.03), opportunist infection (0.90; 5.04; 8.48), late infection (8.3; 22.16; 36.05)
and death rate increased over time (p<0.001 for all). In a multivariate Cox regression analysis, the
potential risk factors for the first IRH were age, time under dialysis before transplant, induction by
antithymocyte globulin induction, corticoid use, and a transplant after 2004. In a repeated events
analysis taking all infections into account, episode of previous IRH was an independent risk factor
for a subsequent event as well as age, time on dialysis prior to transplant, induction by
antithymocyte globulin induction, corticoids, and mycophenolate mophetil use.
CONCLUSIONS: The incidence rate of IRH increases over time. This higher incidence
might be related to different patient profile and immunosuppressive protocols including
antithymocyte globulin induction.
MORE POST Tx

What mean of Sterilization
process that eliminates (removes) or kills (deactivates) all
forms of life and other Biological agents(such as prions,
as well as viruses which some do not consider to be
alive but are biological pathogens nonetheless),
including transmissible agents (such as fungi, viruses,
spore forms, unicellular eukarutik organisms such as
plasidium, etc.) present in a specified region, such as a
surface, a volume of fluid, medication, or in a
compound such as biological cultural media.
Sterilization can be achieved with one or more of the
following: heat, chemicals, irradiation, high pressure,
and filtration.
Sterilization of Medical Products BioAdequacy

Sterilization History
Ancients' believed that demons are the cause
of infection and diseases
Egyptians (3000 BCE)
Antiseptics such as pitch or tar and resins widely
used in embalming bodies

Hippocrates (460-377 BCE)
First separation of philosophy from medicine
and made irrigation of wounds with wine &
boiled water.
Middle Ages(900-1500CE)
-Starting dealing with infected places by
*Cleansing solutions *Aeration *Sulfur Fumes

Denis Papin(1680)
First pressure cooker which is beginning of
Idea of steam under pressure.
-concept of superheated steam to
121C under pressure.

Modern Era
Louis Pasteur(1862)
(father of modern microbiology)
-Develop disinfection and sterilization process
-Pasteurization process for food spoilage slowing.
Earnest Von Bergmann(1885)
-First using of steam sterilization and
Develop aseptic surgery.

Modern Era
Auto Clavation (1933)
Microwave Radiation(1947)
Ethylene Oxide Sterilization(ETO) 1940
Ionizing radiation(1940)
Using cobalt 60 as source of radiation

William Rutala(1994)
 American physician set the ideal sterilization method:
1-Highly Efficiency
2-Rapid Effect
3- Non Toxic
4- Strong Penetration
5-Organic material resistance
6-Adaptability
7-Monitoring Capability
8- Material compatibility
9- Cost effective

Dialysis Products Sterilization
Selection Of
Sterilization Process
Safety Of process to
patients, Staff &
Environment
Impact On Patient
Cost
Product Geometry
Stability Of Product
Components
Legal
Stipulations
Sterile Product is free from any viable micro organism

Ethylene Oxide(ETO)
ETO is a highly reactive gas which reacts chemically
with proteins and nucleic acids (Alkylation), thus
killing microorganisms.
ETO normally diluted with inert gas to avoid
explosion.
ETO provide many advantages:
1- Cost Effective
2- availability of sterilization in outer package
3-Suitable for many materials

Ethylene Oxide(ETO)
Owing to danger of ETO toxicity there are
many legal regulations for its use:
ETO residue know as a cause of many allergic
reactions
Egypt now is ETO free Country from 2013
Authority Maximum ETO residue
European Pharmacopeia 10 ppm
Italy and France 2 ppm
Germany MOH No ETO residue

Clinical Trials & Case Reports
• Nephrol Dial Transplant (2006) 21: 2966–2970
doi:10.1093/ndt/gfl332
Advance Access publication 19 July 2006
Case Report
Fatal acute systemic hypersensitivity reaction during haemodialysis
Maria Dolores Arenas1, Enrique Niveiro2, Analı´a Moledous1, Maria Teresa Gil1
Anaphylaxis is a severe, life-threatening, generalized or systemic form of
hypersensitivity.
The majority of reported cases have been due to sensitization to ethylene oxide (ETO)

Clinical Trials & Case Reports
• Nephrol Dial Transplant (2003) 18 [Suppl 5]: v41–v44
DOI: 10.1093/ndt/gfg1044
Clinical importance of biocompatibility and its effect on haemodialysis treatment
• Karel Opatrny´ Jr
Department of Medicine I, Charles University Medical School, Pilsen, Czech Republic
Ethylene oxide (ETO) and HSR(Hypersenstivity Reactions)
While rare, HSRs are a feared complication of haemodialysis considering their potential for a serious
and eventually fatal course. In the 1980s, their incidence was 3.3/1000 patients/year with capillary,
and 0.3/1000 patient/year with plate dialysers. This substantial difference was due to ETO used for
dialyser sterilization, which remained in the potting material of capillary dialysers. ETO forms
conjugates with serum albumin (ETO–HSA) which act like antigens.
In the 1980s, when ETO was widely used for dialyser sterilization, two-thirds to three-quarters of HSR
patients had antibodies against the ETO–HSR complex.

Gamma Ray Sterilization

 Gamma rays are a form of electromagnetic
radiation—like x-rays, but with higher energy. The
primary industrial sources of gamma rays are
radionuclide elements such as Cobalt 60, which emit
gamma rays during radioactive decay. Gamma rays
pass readily through plastics and kill bacteria by
breaking the covalent bonds of bacterial DNA. They
are measured in units called kiloGrays (kGy)

Advantages
Avoidance of allergic Reactions associated
with ETO.
Simple process control with the radiation
dose.
Less restrictions in product and package as
gamma radiation passes closed hollow spaces.

Disadvantages
 Changes in color, tensile strength and elasticity of
plastic materials indicating material decomposition.
 Numerous chemical and physical changes in materials.
 Partial degeneration of plastic polymers.
 Formation of toxic products as in polyurethan potting
material of dialyzers may develop 4,4-methylene
dianaline (MDA) which is carcinogenic material.
 Change in pores size, shapes and geometry affecting
clearance and UF of dialyzers.

Clinical trial on Cytotoxic Effect of
different sterilization methods

Teresa Rodon, DuPont UK
Ernst Poppe, DuPont INTL SA
Alexandra Fabbro, DuPont INTL SA
Tom Baltus, E.I. DuPont Canada Co.
July, 2010
The effect of common sterilization techniques on the
mechanical properties of DuPont Performance Polymers
Special Control (SC) and Premium Control (PC) grades
The main disadvantage associated with gamma irradiation concerns the potentially damaging
effects of gamma rays on the product, particularly those products that contain polymeric
components
Gamma Sterilization

The Effect of Radiation on a Variety of
Pharmaceuticals and
Materials Containing Polymer
• Mine Silindir and Yekta Özer
• Parentral Drug association Journal
, 2012 PDA J Pharm Sci and Tech:966,84

• ABSTRACT: The interaction of radiation, whether it has natural or artiﬁcial,
electromagnetic or particle-type characterizations, with materials causes different
effects depending on the dose and type of radiation and physicochemical
properties of the material. In the medical ﬁeld, understanding the effect of
radiation on a variety of materials including pharmaceuticals, medical devices,
polymers as biomaterials, and packaging is crucial. Although there are many kinds
of sterilization methods,
• the use of radiation in sterilization has many advantages such as being a
substantially less toxic, safer terminal sterilization method. Radiosterilization is
sterilization with an ionizing radiation such as gamma rays or electron beam (e-
beam), the latter being a newer but less-frequently used technique.
• However, the need for large facilities with proper radiation protections for
personnel and the environment from the effects of radiation and radioactive
wastes makes this procedure highly costly.
• The effects of radiation on materials, especially pharmaceuticals and polymer-
containing medical devices, cause degradation or chemical changes.
• The effects of radiation on a variety of different materials is a growing research
area that can create safer techniques that reduce radiation damage and increase
cost-effectiveness in the future.

Steam Sterilization

Steam Sterilization(Auto Clavation)
 Pressurized steam at high temperature killing
microorganisms by denaturation of cell wall and
proteins.
 15 minutes on 121C is recommended
 Steam Sterilization overcomes disadvantages of ETO &
Gamma Sterilization
 No residual content of sterilizing agent in product.
 Excluded damaging changes in materials
 Environmental friendly procedures without toxic or
radioactive substances.

Steam Sterilization(Auto Clavation)
Disadvantages
Components of killed microorganisms (in
many these are heat resistant endotoxin and
other pyrogen) remain in the product and may
reach to patient.
Same thing for impurities which may present
in product before undergoing sterilization.

In Line Steam Sterilization
Steam arising from pure, sterile water
continuously flows through blood and
dialysate side of each dialyzer in special
sterilization circuit.
Continuity of this process ensure that every
point of each dialyser is at 121 C at least 15
minute,
Pressure holding test applied to ensure
integrity of individual fibers.

IN- Line Steam sterilization

Excellent Biocompatibility
Minimized risk of leakage and raptures
Dry delivered dialyzer
Sterile caps preserve sterility of dialyser
Pyrogen free product
Fibre Integrity Testing
No pore filling materials
Reduced pre rinsing cost and time
Adequate Patient Care in the Most Biocompatible Way

Solute Clearance - Diffusion
•Small (< 500d) molecules
cleared efficiently
•Concentration gradient
critical
•Gradient achieved by
countercurrent flow
•Principal clearance mode
of dialysis techniques

Solute Clearance – Ultrafiltration & Convection
(Haemofiltration)
• Water movement “drags” solute
across membrane
• At high UF rates (> 1L/hour) enough
solute is dragged to produce
significant clearance
• Convective clearance dehydrates the
blood passing through the filter
• If filtration fraction > 30% there is
high risk of filter clotting*
• Also clears larger molecular weight
substances (e.g. B12, TNF, inulin)
* In post-dilution haemofiltration
ULTRFILTRATION
•movement of fluid through a semipermeable membrane
•a membrane’s effectiveness to ultrafiltrate fluid is described by the
ultrafiltration coefficient (KUF), which is QUF/ deltaP (volume of
ultrafiltrate per unit time, divided by the pressure gradient across the
membrane)

Cardioprotective Haemodialysis
Difference- the Pore Size

Cardioprotective Haemodialysis
Diffusive elimination 
conventional haemodialysis
only
Low hydraulic permeability (low High hydraulic permeability
ultrafiltration coefficient) (high ultrafiltration coefficient)
Elimination by diffusion and
convection  suitable for
Haemodialysis, Haemofiltration
and Haemodiafiltration
Low-Flux
Smaller pores: average
diameter of 1 nm
(=0.000000001 m)
Cut-off point ≈ 5 kDa
No elimination of uraemic
toxins ˃ 5 kDa
High-Flux
Bigger pores: average
diameter of 3 nm
(=0.000000003 m)
Cut-off point ≈ 30-50 kDa
Elimination of uremic toxins
similar to natural kidney

78
•High-flux filters showed
32% risk reduction for all-cause death in
patients on dialysis for >3.7 years
20% risk reduction for cardiac death in the
full study group
52% risk reduction for cerebrovascular death
in patients without such vascular disease at
study start
1)HEMO (Hemodialysis Study) JASN 2003

Delmez JA et al.
Am J Kidney Dis (2006); 47:131-138
“Cerebrovascular disease in maintenance hemodialysis patients: results of the HEMO study”
• Secondary analysis of a prospective, randomised and controlled trial with 1,846 patients.
• High-flux was associated with decreased CBVD mortality in those on
haemodialysis therapy for longer than 3.7 years.
High-Flux Membranes and
Morbidity

2)Korean study Compared with hemo Study
The HEMO study showed that there was no statistically significant interaction between
baseline residual renal function and the type of flux intervention with respect to all-
cause mortality although there was a trend towards decreased mortality in patients with
lesser residual renal function .
They reported that all-cause mortality rates were not significantly different between
patients with residual urea clearance ≤0.24 ml/min and those with residual urea
clearance >0.24 ml/min (P = 0.24) which is not consistent with our results.
• There are a number of possible explanations for this discrepancy.
• First, it should be noted that the HEMO study only included patients with
residual urea clearance <1.5 ml/min/35L of urea. Because the impact of high-
flux dialysis on mortality may be less apparent in patients with greater
residual renal function, the exclusion of patients with greater residual renal
function may be a confounding factor in comparing the impact of high-flux
dialysis on mortality according to residual renal function.
• Second the HEMO study included HD patients in which dialyzers were reused.
Reuse of dialyzers may be associated with structural damage of the
membrane and a reduced permeability to middle molecules Therefore, reuse
of dialyzer also may be a confounder to determine the impact of dialyzer
membrane flux on mortality.

A total of 893 patients with 24 h-residual urine volume ≥100 ml and 913
patients with 24 h-residual urine volume <100 ml were included in this study.
Comparison of the Impact of High-Flux Dialysis on Mortality in Hemodialysis
Patients with and without Residual Renal Function
• Hyung Wook Kim, et a,lSeoul, Korea,2014

Table 3. Multivariate Cox regression analysis of mortality in study populations.

83
• Randomized, parallel groups with long-term follow-up
• 738 new ESRD patients enrolled,647 patients eligible for analysis
• Study duration 7.5 years (1999-2006)
•76% of patients at risk by having S-albumin ≤4
g/dl (specific inclusion criteria) -24 % diabetics
• Dialyzer UF coeff: 45±9 vs. 10±3 ml/h,mmHg; no reuse
3)MPO (Membrane Permeability Outcome Study)
High-flux filters showed
37% risk reduction for all-cause death in new patients
with low serum-albumin levels
significant survival benefit in new patients with
diabetes

4)Other Studies:
Improved Relative Risk of mortality with High Flux
0.63
0.62
0.65
0.58
0.61
0 0,2 0,4 0,6 0,8 1
Reference
Koda, 1997
Woods, 2000
Port, 2001
Chauveau, 2005
Krane, 2007
Low Flux RR=1

Tattersall et al, NDT 2007ERA-EDTA European Best Practice
Guidelines for HD – Dialysis strategies
2.Flux and convection
Guideline 2.1
The use of synthetic high-flux membranes should be considered to
delay long-term complications of HD therapy. Specific indications
include:
a) to reduce dialysis-related amyloidosis
b) to improve control of hyperphosphataemia
c) to reduce the increased cardiovascular risk
d) to improve control of anemia
Guideline 2.2
In order to exploit the high permeability of high-flux membranes, on-
line HDF or HF should be considered.
The exchange volume should be as high as possible, with consideration
of safety.

Ledebo I , Blankestijn P J NDT Plus 2010;3:8-16
© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA].

Gloobal,Both Sexes,all
ages,2013,Deaths
4 fold increase in CKD deaths
in next 25 years

Multiple Metrics for health
-)YLL+YLD=DALY +)HALE
Christopher Murray
,ASN2015

Mebranes sterilflux hani hafez may2017

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