Nephrology Core B MEIJERS

7/23/2019 Nephrology Core B MEIJERS

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HEMODIALYSIS par t 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







• Urea kinetics

A brief history of dialysis

John Jacob Abel, 1857-1938John 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’


Georg Haas (1886 – 1971)

Giessen, Germany

‘Blood washing’

•Tool:


Collodium

• Saline solution

• Heparin anticoagulation

No survival benefit




Jan Kolff (1911 – 2009)

Groningen, the Netherlands

Dialysis

• Tools:


Cellulose

• Saline solution

• Heparin anticoagulation

• Increased blood volume

Survival benefit


Kolff ’s rotating drum kidney


http://localhost/var/www/apps/conversion/tmp/scratch_1//commons.wikimedia.org/wiki/File:KolfDrumKidney.jpg




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








• Urea kinetics

Diffusion theories

Adolf Fick, 1829-1901



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



Diffusion hollow fiber

Relative concentration

0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

Clearance concept


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



blood water urea clearance



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



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



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 K d

• Practical use in the clinics is limited

(most modern membranes have high KoA)


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 dia lys is , 4th edition


Case 1Your 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)



‘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


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






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



From diffusion to filtration


Osmotic gradient using hypertonic dialysate

Ventouri-type syphon

at effluent line

Pressure cooker


Pressure

PressureUF

Kuf = Ultrafiltration coefficient

= dependent on membrane characteristics

= permeability of membrane to water

= volume / time ∙ pressure Units = mL of fluid / hour ∙ mmHg

http://www.google.be/url?sa=i&rct=j&q=&source=images&cd=&cad=rja&docid=H5LURx-VhbpQ-M&tbnid=UqW5QwGXOIvT-M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.toonpool.com%2Fcartoons%2Funder%2520pressure_33330&ei=Z6e9UbvoErKo0AWImIFg&bvm=bv.47883778,d.d2k&psig=AFQjCNEgeY-K-RlqS4nI1JweLBDzdRYzLQ&ust=1371469830115475



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



Hemodynamics

Hemodynamics

Pressure alarms (approximative)1. Arterial pressure < - 200 mmHg

2. Systemic pressure > 400 mmHg

(pre-filter pressure)

3. Venous pressure > 200 – 250 mmHgCourtesy of GAMBRO

Hemodynamics



Hemodynamics

Jean Louis Poiseuille

1797 - 1869

Pressure loss

Pressure loss

PressureBlood Inlet

PressureDialysate outlet

PressureBlood Outlet

PressureDialysate 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 modelsUnits = 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)

http://en.wikipedia.org/wiki/File:Poiseuille_abstraction.svg

http://en.wikipedia.org/wiki/File:Poiseuille.jpg



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



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




RBC

Hemofiltration

Plasma water

RBC

Hematocrit 30 % Hematocrit 37 %

Filtration 30% ofplasma water

Hemodynamics

20%

30%

40%

50%

60%

70%

0 20 40 60 80 100 120 140 160

ultrafiltration, ml/min

h e m a t o c r i t a t d i a l y z e r o u t l e t

Hemodynamics

Jean Louis Poiseuille1797 - 1869




http://en.wikipedia.org/wiki/File:Poiseuille_abstraction.svg




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: [email protected]

Middilution HDF



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




0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

Dialysate composition


0 1


Blood composition

mmol/l

Na+ 135 – 145

K+ 3,5 – 5

Cl- 98 – 107

HCO3- 22 - 28

Ca2+ 1,1 – 1,3P 0,74 – 1,52

Mg2+ 0,65 – 1,05

mg/dLGlucose 65 – 100


mmol/l

Na+ 130 - 150

K+ 0 - 3

Cl- 109

HCO3- 20 - 40

Ca2+ 1,0 – 1,75P 0

Mg2+ 0,5

mg/dLGlucose 100

Dialysate preparation

Sodium, chloride,

calcium, magnesium,potassium, sugar, …

Water..

‘Leuvens stadswater’



Dialysate is electrolytes…


23 kg 2,5 kg


http://localhost/var/www/apps/conversion/tmp/scratch_1//upload.wikimedia.org/wikipedia/commons/6/64/CentralDialysatedelivery.JPG



NaCl NaHCO3

110 mEq Na( = 12 mS )

140 mEq Na30 mMol HCO3

( = 14 mS )

1:400

1,25 ml/Min


Conductivity/ Conductance

• Measure of electricity conduction

• Movement of electrolytes (charged atoms)

• SI unit : Siemens / meter

• Used as measurement of electrolyte composition of dialysa te

Case 2The dialysis nurse comes to see you and tells you that the dialysismonitor gives the alarm: ‘Low conductivity’

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


Dialysate is electrolytes + H 2 0

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)

http://localhost/var/www/apps/conversion/tmp/scratch_1//upload.wikimedia.org/wikipedia/commons/9/9d/Conductimetrie-schema.png



CONTAMINANT mg/LCalcium 2Magnesium 4

Potassium 8

Sodium 70 Antimony 0,006

Arsenic 0,005Barium 0,10

Beryllium 0,0004

Cadmium 0,001Chromium 0,014

Lead 0,005Mercury 0,0002

Selenium 0,09Silver 0,005

Aluminium 0,01Chloramines 0,10Free chlorine 0,50Copper 0,10

Fluoride 0,20

Nitrate (as N) 2,0Sulphate 100Thallium 0,002Zinc 0 10

CONTAMINANT mg/LCalcium 2Magnesium 4

Potassium 8Sodium 70

Antimony 0,006 Arsenic 0,005Barium 0,10Beryllium 0,0004

Cadmium 0,001

Chromium 0,014Lead 0,005Mercury 0,0002Selenium 0,09

Silver 0,005Strontium 0,01

Aluminium 0,01Chloramines 0,10Free chlorine 0,50

Copper 0,10Fluoride 0,20

Nitrate (as N) 2,0Sulphate 100

Thallium 0,002Zinc 0 10

CONTAMINANT mg/L

Calcium <2Magnesium <2Potassium <2Sodium <50

Antimony -

Arsenic -Barium -Beryllium -

Cadmium -

Chromium -Lead -

Mercury <0,001Selenium -

Silver - Aluminium < 0,01

Chloramines -

Free chlorine <0,1Copper < 0,01

Fluoride <0,20Nitrate (as N) <2,0

Sulphate <50Thallium -Zinc <0,10Heavy metals <0,1

Chloride <50

ISO 23500 draft (2004) AAMI RD52 (2004)

Ph Eur 5th ed 2005CHEMISTRY

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)



Endotoxin

Cell wallGram 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





Sterility Assurance Level (SAL)

A SAL of 10-6 denotes a probability of not more than one viablemicroorganism 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 3You 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…


Ultrapure dialysate in perspective


Stop HDF/ high flux HD

Use low flux HD membranes only

Thorough disinfection / sterilisation



Dialyzer membranes

Courtesy of Vienken, Fresenius Medical Care

Dialyzer membranes


Dialyzer membranes




Dialyzer membranes


Dialyzer membranes


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)



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



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


0 1

Blood inlet

Dialysate outlet

Blood outlet

Dialysate inlet

= C0

Cend


RR = (Cend - C0) / C0

Clearance

Kd = RR ∙ Qb

A: Volume 40L Cin

Cout


RR = (Cin - Cout) / Cin = 1

Clearance

Kd = RR ∙ Qb = Qb

Qb = 10 L / uur

Urea kinetics

http://www.google.be/url?sa=i&rct=j&q=&source=images&cd=&cad=rja&docid=HckYBxrWhsGY2M&tbnid=Qm7Z3HP2wRooXM:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.cypresstechnosolutions.com%2FAboutUs.aspx&ei=YhXCUaGAEsSW0AXr6YGACA&bvm=bv.48175248,d.ZWU&psig=AFQjCNEOT1Hkihe8WGpue68Mk1CqeWIUIg&ust=1371760260218441

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A: Volume 20L Cin

Cout



ClearanceKd = 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 = 1.0Volume A contains no solutes

B: Volume 40L

A: Volume 0L

Urea kinetics

A: Volume 40L Cin

Cout



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



Urea kinetics


Urea kinetics


Urea kinetics


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

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Nephrology Core B MEIJERS