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HEMODIALYSIS part I

Principles, techniques, materials and quality control

Björn Meijers

• Introductory history of dialysis

• Diffusion, theoretical and practical considerations

• Filtration, theoretical considerations

• Filtration, practical considerations

• Urea kinetics

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• Introductory history of dialysis

• Diffusion, theoretical and practical considerations

• Filtration, theoretical considerations

• Filtration, practical considerations

• Urea kinetics

A brief history of dialysis

John Jacob Abel, 1857-1938

John Hopkins University

• Study of blood constituents

• Isolation of epinephrine

• Crystalisation of insulin

• Tool:

• semi-permeable membrane

(Celloidin)

• Saline solution

• Hirudoid anticoagulation

• Application:

• Blood purification

• ‘vividiffusion’

A brief history of dialysis

Georg Haas (1886 – 1971)

Giessen, Germany

‘Blood washing’

•Tool:

• semi-permeable membrane

Collodium

• Saline solution

• Heparin anticoagulation

No survival benefit

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A brief history of dialysis

Jan Kolff (1911 – 2009)

Groningen, the Netherlands

Dialysis

• Tools:

• semi-permeable membrane

Cellulose

• Saline solution

• Heparin anticoagulation

• Increased blood volume

Survival benefit

A brief history of dialysis

Kolff’s rotating drum kidney

A brief history of dialysis

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Dialysis membranes

Kolff-Graham kidney

• 1956

• Disposable

• Priming volume 1.2 – 1.4 L

• Price $59.00

Dialysis membranes

Kiil kidney (1960)

Priming volume 300 mL

Dialysis membranes

Capillary kidney (1964-1967)

Cellulose Acetate

Capillary kidney (1977-1978)

Cuprophane

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A brief history of dialysis

• Introductory history of dialysis

• Diffusion, theoretical and practical considerations

• Filtration, theoretical considerations

• Filtration, practical considerations

• Urea kinetics

Diffusion theories

Adolf Fick, 1829-1901

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Diffusion theories

Albert Einstein, 1879-1955

• Blood

• Access to blood compartment

• Anticoagulation procedures

• Hemodynamics

• Dialysis membrane

• Shape

• Diffusion characteristics

• Blood compatibility

• Dialysate

• Composition

• Anorganic and organic impurities

• Microbial contamination

Diffusion in dialysis

Dialysis membranes

Kolff-Graham Kiil Capillary

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Diffusion hollow fiber

Relative concentration

0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

Clearance concept

Relative concentration

0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

= C0

Cend

Reduction ratio (RR)

RR = (C0 - Cend) / C0

Clearance

Kd = RR ∙ Qb

Plasma

(1 – hematocrit)

Erythrocytes

Plasma water

(93% of plasma)

RBC water

(72% of RBC)

Blood is a complex solution…

Effects of blood characteristics

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blood water urea clearance

Plasma water

(93% of plasma)

RBC water

(72% of RBC)

Blood urea nitrogen / urea

• Measured as plasma concentration

• ‘Free’ diffusion in/ out of RBC

• Blood water flow rate

= (0.93 ∙ (1 – Hct) + 0.72 ∙ (Hct)) ∙ Qb

≈ 0.9 ∙ Qb

• Blood water urea clearance

≈ 0.894 ∙ K

blood water clearance

Plasma water

(93% of plasma)

RBC water

(72% of RBC)

Blood creatinine and phosphorus

• Measured as serum concentrations

• ‘hindered’ diffusion in/ out of RBC

• Blood water flow rate

= (0.93 ∙ (1 – Hct) + 0.72 ∙ (Hct)) ∙ Qb

≈ 0.9 ∙ Qb

• Increasing hematocrit reduces mass

removal of creatinine and phosporus

• Effectsize up to more than 10%

Effects of blood characteristics

Effect of blood flow on Clearance

• Theoretical : K = RR ∙ Qb

• In reality :

Depner,

Hemodial Int 2005

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Membrane characteristics

KoA: Dialyzer Mass Transfer Area Coefficient

• Maximum possible clearance

- of a given dialyzer (clearance Ko mutiplied with area A)

- at infinitely large blood flow rate

- at infinetely large dialysate flow rate

• Units: mL/min

• Kd can be estimated from KoA, Qb and Qd

• Nomograms allow for rapid estimation of Kd

• Practical use in the clinics is limited

(most modern membranes have high KoA)

Membrane characteristics

KoA K

(Qb 200 ml/min)

K

(Qb 400 mL/min)

% change K

400 137 173 + 26 %

800 166 235 + 42%

Depner, Hemodial Int 2005; Daugirdas et al., Handbook of dialysis, 4th edition

Membrane characteristics

Case 1 Your team performs dialysis at the ICU. The intensivist suggests that

‘you need to learn how to dialyse your patients’ as the urea reduction

ratio is not satisfying.

Review of the previous dialysis session:

• No significant issues with vascular access

• Qb 200 mL/min, Qd 500 mL/min

• Filter (manufacterer X), membrane area 1,4 m², KoA 850 mL/min

You are allowed to change one factor (excluding dialysis time). What

would have the most profound effect on the urea reduction ratio?

1. Increase membrane area (KoA)

2. Increase blood flow (Qb)

3. Increase dialysate flow (Qd)

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‘The rule of thumb..’

Courtesy of GAMBRO Lundia

Urea diffusion vs. uremia

Urea clearance (mL/min)

140 278 (FX 1000)

‘From the beginning all dialysis systems were and are designed

as urea removal machines’

TW. Meyer, Stanford University 2009

Urea diffusion vs. uremia

A. Babb, R. Popovich, G. Cristopher and B. Scribner

‘For a number of years we have been speculating that so-called “middle

molecules” play an important role in the toxicity of uremia. By middle

molecules we mean molecules that because of their size are very slowly

dialyzable when compared to urea. This very low dialyzability is due almost

entirely to a very high membrane diffusion resistance…’

Trans Am Soc Artif Organs, 1971

Water-soluble toxins

Potassium

Urea

Creatinin

Large molecules/proteins

β2-microglobulin

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Urea diffusion vs. uremia

Urea diffusion vs. uremia

Sieving coefficient ≠ diffusive clearance !

Courtesy of Fresenius

Diffusion principles

• Solutes can be removed by diffusion

• Diffuse removal can save lifes

• Removal can be quantified as clearance

• Factors determining clearance are

• Blood flow and composition

• Membrane characteristics (KoA, sieving coefficient)

• Dialysate flow

• Relative clearance is determined by laws of physics

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From diffusion to filtration

From diffusion to filtration

Osmotic gradient using hypertonic dialysate

Ventouri-type syphon

at effluent line

Pressure cooker

From diffusion to filtration

Pressure

Pressure UF

Kuf = Ultrafiltration coefficient

= dependent on membrane characteristics

= permeability of membrane to water

= volume / time ∙ pressure

Units = mL of fluid / hour ∙ mmHg

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Hemodynamics

Courtesy of GAMBRO Lundia

Hemodynamics

Courtesy of GAMBRO

Hemodynamics

1. Arterial pressure

2. Systemic pressure

(pre-filter pressure)

3. Venous pressure

Courtesy of GAMBRO

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Hemodynamics

Hemodynamics

Pressure alarms (approximative)

1. Arterial pressure < - 200 mmHg

2. Systemic pressure > 400 mmHg

(pre-filter pressure)

3. Venous pressure > 200 – 250 mmHg Courtesy of GAMBRO

Hemodynamics

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Hemodynamics

Jean Louis Poiseuille

1797 - 1869

Pressure loss

Pressure loss

Pressure

Blood Inlet

Pressure

Dialysate outlet

Pressure

Blood Outlet

Pressure

Dialysate inlet

Ultrafiltration

Ultrafiltration

TMP = Trans-Membrane Pressure

= calculated by dialysis monitor

= dependent on hemodynamics (vascular access)

= dependent on hardware (which pressure sensors available)

= dependent on used definitions

= differs between suppliers and between models

Units = mmHg

UF = TMP ∙ Quf

→ effect Δ TMP on UF depends on Quf

→ If Quf is high: TMP-regulated UF is difficult

→ Dialysis monitors don’t ‘know’ Quf

ULTRAFILTRATION CONTROL (using balance chambers)

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TMP calculations

Ultrafiltration

Backfiltration

High Quf ≈ Backfiltration

High Quf ≈ Need for pure(r) dialysate

From ultra- to hemofiltration

Daugirdas et al., Handbook of dialysis, 4th edition

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From ultra- to hemofiltration

SOLVENT DRAG

Hemofiltration

Plasmafiltration

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pre-dilution

Outflow filtrate

Outflow blood

Inflow blood

Hemofiltration

Hemofiltration

Predilution ≈ reducing serum concentrations

≈ reducing small solute clearance

(differential effect on protein-bound solutes)

post-dilution

Outflow filtrate

Outflow blood

Inflow blood

Hemofiltration

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Plasma water

(93% of plasma)

RBC

Hemofiltration

Plasma water

RBC

Hematocrit 30 % Hematocrit 37 %

Filtration 30% of

plasma water

Hemodynamics

20%

30%

40%

50%

60%

70%

0 20 40 60 80 100 120 140 160

ultrafiltration, ml/min

he

ma

toc

rit

at

dia

lyze

r o

utl

et

Hemodynamics

Jean Louis Poiseuille

1797 - 1869

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Hemofiltration in the past…

Courtesy of Lee Henderson, 2000

pre-dilution

Outflow filtrate

Outflow blood

Inflow blood

From HF to HDF

Inflow dialysate

post-dilution

Santoro A et al. Nephrol. Dial. Transplant. 2007;22:2000-2005

© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights

reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Middilution HDF

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Filtration principles

• Ultrafiltration depends on pressure differences

• Ultrafiltration depends on membrane Quf

• Filtration removes solutes by solvent drag

• Postdilution is limited due to hemoconcentration

• Predilution is ‘unlimited’, but less effective (dilution)

Materials

• Dialysate

• Composition

• Anorganic and organic impurities

• Microbial contamination

• Dialysis membrane

• Sterility

• Materials and blood compatibility

• Dialysis monitors

Materials

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Relative concentration

0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

Dialysate composition

Relative concentration

0 1

Dialysate composition

Blood composition

mmol/l

Na+ 135 – 145

K+ 3,5 – 5

Cl- 98 – 107

HCO3- 22 - 28

Ca2+ 1,1 – 1,3

P 0,74 – 1,52

Mg2+ 0,65 – 1,05

mg/dL

Glucose 65 – 100

Dialysate composition

mmol/l

Na+ 130 - 150

K+ 0 - 3

Cl- 109

HCO3- 20 - 40

Ca2+ 1,0 – 1,75

P 0

Mg2+ 0,5

mg/dL

Glucose 100

Dialysate preparation

Sodium, chloride,

calcium, magnesium,

potassium, sugar, …

Water..

‘Leuvens stadswater’

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Dialysate is electrolytes…

Dialysate is electrolytes…

23 kg 2,5 kg

Dialysate is electrolytes…

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NaCl NaHCO3

110 mEq Na ( = 12 mS )

140 mEq Na 30 mMol HCO3

( = 14 mS )

1:400

1,25 ml/Min

Dialysate is electrolytes…

Conductivity/ Conductance

• Measure of electricity conduction

• Movement of electrolytes (charged atoms)

• SI unit : Siemens / meter

• Used as measurement of electrolyte composition of dialysate

Case 2 The dialysis nurse comes to see you and tells you that the dialysis

monitor gives the alarm: ‘Low conductivity’

He/she asks if it’s OK to override the alarm?

Dialysate is electrolytes…

Dialysate is electrolytes + H20

Tap Water

• is the basis of the dialysate

• cannot be used directly due to contaminants

• is centrally prepared and distributed

Reverse osmosis (semi-permeable membrane)

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CONTAMINANT mg/L Calcium 2

Magnesium 4

Potassium 8

Sodium 70

Antimony 0,006

Arsenic 0,005

Barium 0,10

Beryllium 0,0004

Cadmium 0,001

Chromium 0,014

Lead 0,005

Mercury 0,0002

Selenium 0,09

Silver 0,005

Aluminium 0,01

Chloramines 0,10

Free chlorine 0,50

Copper 0,10

Fluoride 0,20

Nitrate (as N) 2,0

Sulphate 100

Thallium 0,002

Zinc 0,10

CONTAMINANT mg/L Calcium 2

Magnesium 4

Potassium 8

Sodium 70

Antimony 0,006

Arsenic 0,005

Barium 0,10

Beryllium 0,0004

Cadmium 0,001

Chromium 0,014

Lead 0,005

Mercury 0,0002

Selenium 0,09

Silver 0,005

Strontium 0,01

Aluminium 0,01

Chloramines 0,10

Free chlorine 0,50

Copper 0,10

Fluoride 0,20

Nitrate (as N) 2,0

Sulphate 100

Thallium 0,002

Zinc 0,10

CONTAMINANT mg/L

Calcium <2

Magnesium <2

Potassium <2

Sodium <50

Antimony -

Arsenic -

Barium -

Beryllium -

Cadmium -

Chromium -

Lead -

Mercury <0,001

Selenium -

Silver -

Aluminium < 0,01

Chloramines -

Free chlorine <0,1

Copper < 0,01

Fluoride <0,20

Nitrate (as N) <2,0

Sulphate <50

Thallium -

Zinc <0,10

Heavy metals <0,1

Chloride <50

ISO 23500 draft (2004) AAMI RD52 (2004)

Ph Eur 5th ed 2005 CHEMISTRY

Dialysate water and H(D)F

DIALYSATE WATER ≠ SUBSTITUTION FLUID

Glorieux et al, Nephrol Dial Transplant 2012

TGEA R 2 A TSA

INCUBATION: 7 days at 17 – 23°C

5,6 x 103 CFU/ml 5,1 x 102 CFU/ml 1,7 x 102 CFU/ml

Colony Forming Units (CFU)

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Endotoxin

Cell wall

Gram negative

Bacteria

• Structural part of the cell outer membrane

• Gramnegative bacteria

• Size: 1200 Dalton to whole cell

• Chemistry: Fat (Lipid A) and carbon hydrate

• Different species – Different Activity

Endotoxin units

Limulus Amoebocyte Lysate (LAL) test

Hemocyaninin

Limulus polymephus LAL reagens Sample (+ dilutions)

1 hour incubation

Degree of clotting

Reporting

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Dialysate water and H(D)F

Glorieux et al, Nephrol Dial Transplant 2012

Sterility Assurance Level (SAL)

A SAL of 10-6 denotes a probability of not more than one viable

microorganism in 1 000 000 sterilized items of the final product

SAL of 10-6/mL equals ...

•1 CFU per 1 000 000 ml

• Dialysate use/session is around 100 liters and more in HDF...

• One session is at least 100 000 ml

• Maximum 10 sessions without risk of bacterial contamination

Case 3 You are the treating physician responsible for a hemodialysis unit with

106 patients. The test results of the dialysate water screening arrive:

198 CFU/mL, LAL test 0,5 units/mL; What would be your action?

a) Close the unit and send the patients to another unit nearby

b) Await the next screening results

c) Something else…

Dialysate water and H(D)F

Ultrapure dialysate in perspective

Glorieux et al, Nephrol Dial Transplant 2012

Stop HDF/ high flux HD

Use low flux HD membranes only

Thorough disinfection / sterilisation

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Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

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Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

Dialyzer membranes

Dialyzer choice considerations

• (High KoA vs. Low KoA)

• High flux vs. Low flux

• Membrane surface area

• Mode of sterilisation (EthO vs. Steam vs. Radiation)

• (Material and biocompatibility)

• (Cost)

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Dialysis monitors

Dialysis monitors

• Hemodynamics: Qb, Pa, Pv, Psyst, TMP

• Dialysate preparation: pipette system, dry concentrate, central distribution

• Substitution solute preparation: ultrapure dialysate

• Ultrafiltration volume control

• Hemodialysis vs. Hemofiltration vs. Hmeodialfiltration (pre/post)

• Single ‘needle’ vs. Double ‘needle’

+ Blood volume monitor

+ Clearance measurements

+ ….

Dialysis monitors

Dialysis monitors

• Class IIb biomedical device (EEC directive 93/42)

• Software connections also are Class IIb biomedical devices

Materials

• Dialysate is composed of electrolytes, sugar and water

• Water purification system as ‘heart of the dialysis unit’

• Dialysate quality monitoring systems (bacteriological and anorganic)

• Choice of dialyser membrane

• Dialysis monitoring is class IIb biomedical device

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Quality control

How do you know you are deliviring good dialysis quality?

• Kt/V as measurement of urea removal

• Limitations of Kt/V

Clearance concept

Relative concentration

0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

= C0

Cend

Reduction ratio (RR)

RR = (Cend - C0) / C0

Clearance

Kd = RR ∙ Qb

A: Volume 40L Cin

Cout

Reduction ratio (RR)

RR = (Cin - Cout) / Cin = 1

Clearance

Kd = RR ∙ Qb = Qb

Qb = 10 L / uur

Urea kinetics

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A: Volume 20L Cin

Cout

Reduction ratio (RR)

RR = (Cin - Cout) / Cin = 1

Clearance

Kd = RR ∙ Qb = Qb

Qb = 10 L / uur

Kt/V = 10 * 2 / 40 = 0.5

B: Volume 20L

Urea kinetics

Cin

Cout

Reduction ratio (RR)

RR = (Cin - Cout) / Cin = 1

Clearance

Kd = RR ∙ Qb = Qb

Qb = 10 L / uur

After 4 hours

Kt/V = 10 * 4 / 40 = 1.0

Volume A contains no solutes B: Volume 40L

A: Volume 0L

Urea kinetics

A: Volume 40L Cin

Cout

Reduction ratio (RR)

RR = (Cin - Cout) / Cin = 1

Clearance

Kd = RR ∙ Qb = Qb

Qb = 10 L / uur

After 4 hours

Kt/V = 10 * 4 / 40 = 1.0

Volume A = 40 L

Volume A contains solutes!

Mathematical (single pool)

spKt/V = - Ln (1 – RR)

Urea kinetics

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Urea kinetics

Daugirdas et al., Handbook of dialysis, 4th edition

Urea kinetics

Daugirdas et al., Handbook of dialysis, 4th edition

Urea kinetics

Daugirdas et al., Handbook of dialysis, 4th edition

Suggested self-study and hemodialysis core curriculum part II

• Equilibrated Kt/V

• Correction for urea generation during dialysis

• Correction for volume removal (reduction of V)

• Correction for residual renal function

• Standardized Kt/V

• Calculation of urea distribution volume

• Protein nitrogen appearance