Hemodiafiltration: Where are we ? Where are we going · Hemodiafiltration: Where are we ? Where are we going ? Controversies conference on Novel techniques and innovation in blood

Hemodiafiltration: Where are we ?

Where are we going ?

Controversies conference on Novel techniques

and innovation in blood purification: How can we

improve clinical outcomes in hemodialysis ? Paris 14-15 October 2011

Where are we going ?

Prof. Bernard Canaud

Néphrologie, Dialyse et Soins Intensifs

Hôpital Lapeyronie – CHRU Montpellier - France

Limits of conventional hemodialysis

Cardiac StunningCardiac StunningCardiac Stunning

Maltolerance of dialysis sessions

StrokeStrokeStroke

Intradialytic HypotensionIntradialytic HypotensionIntradialytic Hypotension

Gut ischemia - TranslocationGut ischemia - TranslocationPoor Quality of LifePoor Quality of Life

Limits of conventional dialysis modalities

Dialysis-related pathology

Outline of the presentation

DefinitionDefinition

EpidemioEpidemioFutureFutureof HDFof HDF

RegulatoryRegulatory

SafetySafetyEfficacyEfficacy

OutcomesOutcomes






OutcomesOutcomes

HDF combines diffusive, convective and

adsorptive clearances in the same module

Inlet Blood Flow Outlet D+UF

1. Ultrafiltration2. Diffusion3. Adsorption

1

3

Substitution

Fluid (SF)

Ultrafilter

100

Outlet Blood Flow

Inlet D+SF

2

2

Hemodiafiltration enhances clearances of middle

and large molecular weight solutes

HD Low Flux HD High Flux HDF HF

DiffusionConvection

Adsorption

Middle molecules removal

Low molecules removal

Total solute clearance in HDF is not the algebraic

sum of solute transfer component

D C

KT = KD + 0.43 QUF + 8.3.10-3 Q2UF + ?

Jaffrin M et al. Artif Organs 1995; 19:1162

KT = KD + Kc+ KAds

KT = KD + 0.50 QUF

ConvectiveDiffusiveTotal Adsorptive

ß2-Microglobulin, Reduction Rate (%)

Convective dialysis dose is a linear function of

substitution volume

On-line HDF substitution volume (ml/min)

15 l15 l 25 l25 l5 l5 l 31 l31 l

Lornoy W et al, Nephrol Dial Transplant. 2000: 15: 49-54Postdilution HDF






OutcomesOutcomes

Prevalence of HDF in Europe in 2010

0.48

0.67

0.550.60

0.70

0.80

0.90

1.00HD treated patients : 294400 Online HDF treated : 50800 Bag HDF treated : 3550

Percent of HDF treated patients, %

0.130.16 0.18

0.13 0.140.18

0.48

0.29 0.30

0.19

0.42

0.33

0.26 0.27 0.28

0.20

0.00

0.10

0.20

0.30

0.40

0.50

Hemodiafiltration Trends by CountryDOPPS 1-4 Sample Patients* (1996-2010)

BE

IT

SW

UK

30%

40%

% of Patients

ANZJP

FR

GE

GE

IT

SP

SP

UK

UK

0%

10%

20%

1(1996-2000)

2(2002-2004)

3(2005-2008)

4(2009-Present)

Study Phase (years)

*Initial prevalent cross-sections who dialyzed 3 times/wk with vintage ≥3 months; DOPPS 4 data are preliminary; ANZ, BE and

SW did not participate in DOPPS phase 1

Facility % of Patients on HDF, by Phase and Country

60%

70%

80%

90%

100%

Facility % of Patients

0%

10%

20%

30%

40%

50%

2 3 4 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 2 3 4 1 2 3 4 3 4 1 2 3 4

Initial prevalent cross-sections who dialyzed 3 times/wk with vintage ≥3 months * p-value <0.05 for test for trend for HDF use over time; †HDF was not used in Japan during DOPPS phases 1 and 2

ANZ BE* FR GE IT SP* SW* UK* AllJP†






OutcomesOutcomes

Hemodialysis/Patient Interaction

ConcentrateWater

Water treatment system

HDF machineHDF machine

Patient

Dialysate

Water treatment system to produce ultrapure

water

Recirculating Loop

DialysisStation

ActivatedCharcoal RO RO

µFilter

µFilter

0.1µ+

Softener µFilter

µFilter

0.1µ+

Pump

Tap Water

Ultrapure dialysis fluid is now recognized as a new

standard of contemporary dialysis

Nephrol Dial Transplant 2002; 17 [Suppl 7]

2002

2009

International Standard ISO 2009

20092009

ISO/FDIS 2009-11663

Non-pyrogenic - Sterile vs Ultrapure

ISO/FDIS 2009-11663

Ultrapure dialysis fluid – Substitution fluid

ISO/FDIS 2009-11663

Water and dialysis fluid tend to the same degree of

microbiological purity

International standards of water

and dialysis fluid

Maximum levelsRegular Water

Ultrapure Water

Ultrapure Dialysis Fluid

Microbial contamination (CFU/ml)

Sensitized methods

<100 <0.1 <0.1

Bacterial endotoxins (IU/ml)

LAL

<0.25 <0.03 <0.03

Water Treatment System, Contamination Levels

Highcontamination

Lowcontamination

.

Tap

Activated

CarbonReverse

Osmosis

HDF machine

Pa

tie

nt

Tap

Water

Softener

µFµF

Storage

Tank

Pump µF

UFWaste

Concentrates

Basic concept of online production of

substitution fluid (infusate)

Patient Ultrafilter

Ultrafilter

Direct connection

No dead space

Patient

Ultrafilter

Frequent disinfection(Heat, Chemical)

Ultrafilter

Online HDF, Modalities of substitution

Dialysate outlet

+ Ultrafiltrate

Dialysate inlet Flu

idB

ala

ncin

gM

odule

Dialysate outlet

+ Ultrafiltrate

Flu

idB

ala

ncin

gM

odule

Infusion pump

Dialysate inlet

- Infusate

Flu

idB

ala

ncin

gM

odule

Sterilizing

ultrafiltersInfusion pump

Post-dilution on-line HDF

Volume of substitution ≈ 25l/ses

Pre-dilution on-line HDF

Dialysate inlet

- Infusate

Flu

idB

ala

ncin

gM

odule

Sterilizing

ultrafilters

Volume of substitution ≈ 50l/ses

On-Line HDF machines approved and labeled

with CE mark

Nikkiso DBB-05

Gambro AK 200S/ Ultra™B.Braun Dialog+

Bellco Formula

FMC 5008FMC 4008 Gambro Innova






OutcomesOutcomes

Safety and efficacy on long term use (1994-

1997)

Canaud B et al, Nephrol Dial Transplant 2000; 15[S1]:60-67

19200 HDF sessions

Total production of substitution fluid 533 594 liters

Infusate bacteriometry (1994-1997)

Canaud B et al, Nephrol Dial Transplant 2000; 15[S1]:60-67

19200 HDF sessions – Mean volume filtrate 24 liters

Total production of substitution fluid 533 594 liters

Microbiological quality of purified water and ultrapure dialysis

fluids for online HDF in clinical routine practice

• Subgroup analysis after enrolment

• 10 centers - One year follow-up• 10 centers - One year follow-up

• 97 patients - 11258 HDF sessions

• 3961 samples

Penne EL et al, Kidney Int. 2009 ; 76: 665-672CONTRAST Dutch Convective Transport Study

Clinical safety is confirmed on a routine

basis and large scale

• One year follow-up

• 97 patients• 97 patients

• 11258 HDF sessions

• No febrile reactions

• No clinical adverse events


Ultrapurity of dialysis fluid is confirmed in

85 to 98% of samples

10 centers

One year follow-up11258 HDF sessions97 patients – 3961 samples


Ultrapurity of infusate is confirmed in 99 to

100 % of samples


Effects of OL-HDF & r-HDF on inflammatory & nutritional markers

Cross-over, randomized multicentre trial

Panichi V et al, Nephrol Dial Transplant 2006; 21: 756-762

25 HD patients

Effects of OL-HDF and r-HDF on inflammatory and nutritional markers

Cross-over, randomized multicentre trial

Panichi V et al, Nephrol Dial Transplant 2006; 21: 756-762

HF-HD OL-HDF HF-HD OL-HDF HFHD

4 months 4 months 4 months 4 months4 months

Effect of HD and HDF on CD14+CD16+ monocytes, TNFαααα, IL6 and inflammatory markers

Cross-over, randomized study (31 HD patients)

CD14+ CD16+

TNFα α α α - IL6

Telomere length

4 months 4 months 4 months 4 months4 months

• Polysulfone membrane

• Ultrapure dialysate

• Same dialysis conditions

Carracedo J et al, J Am Soc Nephrol. 2006; 17: 2315

OL-HDF reduces proinflammatory CD14+CD16+ monocyte-derived

dendritic cells

Carracedo J et al, J Am Soc Nephrol. 2006; 17: 2315






OutcomesOutcomes

� Treatment schedule

� 3 sessions of 4 hours weekly (minimum)

� Longer or more frequent (possible)

� Highly permeable synthetic membrane

� Large surface area > 1.8 m2

High-Efficiency on-line HDF. What does it means?

� Ultrapure bicarbonate dialysis fluid

� High blood flow (effective QB: 350 - 400 ml/min)

� High dialysate flow (500-700 ml/min) �� diffusive dose

� Large volume of substitution �� convective dose

� Post-dilution (Qsub : 100 ml/min, 24 l / session)

� Pre-dilution (Qsub : 200 ml/min, 48 l / session)

� Mixed dilution (Qsub : 150ml/min, 36 l/session)

Distribution of Mean Replacement Fluid Volume for Patients on

HDF, by Country

30

35

40

45

50 Percentile

95th

75th

50th

25th

5th

Volume of replacement fluid (Liters)

0

5

10

15

20

25

ANZ50

BE86

FR184

GE142

IT270

JP73

SP56

SW129

UK69

All1059

Country across phase 1 - 3

Initial prevalent cross-sections who dialyzed 3 times/wk with vintage ≥3 months;HDF not used in the US and Canada

Middle molecules removal in ol-HDF vs LF-HD vs HF-HD

69,1 70

54,2

60,6

72,1

63,5

75,4

62,7

80,9

81,682,7

60

80

100LF-HD HF-HD Ol-HDF

HDF post 26.8l/sPercent reduction per session (%)

4,3

24,5

0

20

40

60

Urea, 60d Creat, 113d Osteoc,5.8kd B2M, 11.8kd Myogl, 16kd

Maduell F et al, Am J Kidney Dis 2002; 40: 582-589

Mean dialysis dose and nPCR in HDF treated

patients with direct dialysis quantification method

Canaud B et al, Am J Kidney Dis 1998; 31:74-80Urea Monitoring, BioStat 1000

HDF vs HFHD: modest increase of urea Kt/V

but significant reduction of circulating β2M

ol-HDF

Movilli E et al, Nephro Dial Transplant. 2011; 0:1-6 ePub May2011

LFHD

ß2-M concentrations is reduced after switching from

HFHD to ol-HDF

Tiranathanagul K et al. Ther Apher Dial 2009; 13: 56-62

High efficiency HDF increases the erythropoietic response to ESA

Vaslaki L et al, Blood Purif 2006; 24: 163-173

70 HD patsHD

HDFHDF

HD24wks 24wks

High efficiency HDF increases the phosphate mass

removal

Lornoy W et al, J Ren Nut 2006; 16: 47-53

22 HD patsHD

HDFHDF

HD

4hrs x 3wk

HF80 - QD800Direct dialysate quantification

Hemodynamic tolerance is improved in HDFHemodynamic tolerance is improved in HDF

Tiranathanagul K et al. Ther Apher Dial 2009; 13: 56-62

ol-HDF in Southeast Asia: 3 years experience

22 HD patients HFHD � ol-HDF

Convective therapies (HF, HDF) reduce intradialytic symptomatic hypotension (ISH)

Total incidence of ISH 7.5% 28950 sessions

Locatelli F et al, J Am Soc Nephrol 2010; 21:1798-1807Italian Multicentric Study RCT

LFHD, HF, HDF Ratio 2/1/1

9.8 to 8.0%

�� 18.4%

10.6 to 5.2%

�� 50.9%7.1 to 7.9%

�� 9.9%

Daily online HDF promotes catch-up growth in CKD children

Fischbach M et al, Nephrol Dial Transplant. 2009;

Normalization of growth curve in children treated by daily

ol-HDF

mean

Fischbach M et al, Nephrol Dial Transplant 2004; 19: 2360-2367

Nocturnal, every-other-day, ol-hemodiafiltration

Time & FrequencyVolume substitution

Maduell F et al, Nephro Dial Transplant. 2011; 0:1-13 ePub 13Sep2011

Intracorporealresistance

Convectivedose

Remarkable effect on phosphate control


Considerable reduction of phosphate binders

consumption


Significant beneficial effect on nutritional

status







OutcomesOutcomes

Outcomes of HDF versus HD

Author, Year HDF vs Comparator Type of study Grading

Wizemann V et al, 2000 HDF vs LFHD RCT Ia

Bosch JP et al, 2006 HDF vs LFHD vs HFHDHistorical prospective

cohortIIb

Canaud B et al 2006 HDF± vs LFHD vs HFHD Historical prospective cohort IIa

Jirka et al, 2006 HDF vs LFHD vs HFHD Historical prospective cohort IIaJirka et al, 2006 HDF vs LFHD vs HFHD Historical prospective cohort IIa

Schiffl H et al, 2007 HDF vs HFHD + UPD RCT Ia

Vinhas J et al, 2007 HDF vs HFHD Prospective controlled study IIb

Panichi V et al. 2008 HDF+/- vs LFHD Prospective controlled study IIa

Santoro A et al, 2008 HF vs HFHD RCT Ia

Tiranathanagul K 2009 HDF vs HFHD Prospective controlled study IIa

Vilar E et al, 2009 HDF vs HFHDHistorical prospective

cohortIIb

Locatelli F et al, 2010 HDF vs HD vs LFHD RCT Ia

Distribution of dialysis modality for prevalent patients

Canaud B et al, Kidney Int 2006; 69: 2087-2093

Mortality risk for patients receiving high efficiency HDF vs. HD is reduced

European Results from DOPPS

��35% hs

��7% ns

Canaud B et al, Kidney Int 2006; 69: 2087-2093

Cardiovascular mortality is reduced in ol-HDF

Panichi V et al. Nephrol Dial Transplant. 2008; 23:2337-2343 RISCAVID Study

Survival is significantly higher in HDF treated patients

RR 0.66 vs 1.0 for HDF

Vilar E et al, Clin J Am Soc Nephrol 2009, ePub

Outcomes of HDF versus HD up to 2011

Author, Year HDF vs Comparator Type of study ββββ2-MAnnual

MortalityHD/HDF

SurvivalGain

Wizemann V et al, 2000 HDF vs LFHD RCT �� 9.5/4.3 =

Bosch JP et al, 2006 HDF vs LFHD vs HFHD

Historical prospective cohort

? �� 45%

Canaud B et al 2006 HDF+/- vs LFHD vs HFHD


? 12.7/8.9 �� 35%

Jirka et al, 2006 HDF vs LFHD vsHFHD


? 14.8/8.2 �� 36%Jirka et al, 2006HFHD cohort

? 14.8/8.2 �� 36%

Schiffl H et al, 2007HDF vs HFHD

+ UPDRCT �� 4.1/4.2 =

Vinhas J et al, 2007 HDF vs HFHDProspective controlled

study? 19.9/8.9 �� 50%

Panichi V et al. 2008 HDF+/- vs LFHDProspective controlled

study�� 13.2/10 �� 15%

Santoro A et al, 2008 HF vs HFHD RCT �� 13.3/12 �� 18%

Tiranathanagul K 2009 HDF vs HFHDProspective controlled

study�� =

Vilar E et al, 2009 HDF vs HFHDHistorical prospective

cohort�� 9/6 �� 34%

Locatelli F et al, 2010 HDF vs HD vs LFHDProspective randomized

controlled study? =

Randomized clinical trials in Europe

evaluating HDF vs HD

Dutch TrialCONTRAST

French TrialHFHD vs HDF

> 65yoCatalonian TrialHFHD vs HDF

Turkish TrialHFHD vs HDF

Italian TrialLFHD vs HF/HDF

LFHD vs HDF350/350

CV eventsMortality

36 months

> 65yo300/300

ToleranceCV eventsMortality

24 months

HFHD vs HDF300/300

CV eventsMortality

24 months

300/300CV eventsMortality

24 months

150/75/75ToleranceMorbidityMortality

24 months

Reported & PublishedCompletedReported at ERA-EDTA

Ongoing Ongoing CompletedReported at ERA-EDTA






OutcomesOutcomes

Focusing on middle molecules…Convective

dialysis dose

Small water soluble solutes Protein-bound solutes Middle moleculesAsymmetric dimethylarginine 3-Deoxyglucosone AdrenomedullinBenzylalcohol CMPF* Atrial natriuretic peptideß-Guanidinopropionic acid Fructoselysine ß2-Microglobulinß-Lipotropin Glyoxal ß-EndorphinCreatinine Hippuric acid CholecystokininCytidine Homocysteine Clara cell proteinGuanidine Hydroquinone Complement factor DGuanidinoacetic acid Indole-3-acetic acid Cystatin CGuanidinosuccinic acid Indoxyl sulfate Degranulation inhibiting protein IMiddle moleculesGuanidinosuccinic acid Indoxyl sulfate Degranulation inhibiting protein IHypoxanthine Kinurenine Delta-sleep-inducing peptideMalondialdehyde Kynurenic acid EndothelinMethylguanidine Methylglyoxal Hyaluronic acidMyoinositol N-carboxymethyllysine Interleukin 1ß Orotic acid P-cresol Interleukin 6Orotidine Pentosidine Kappa-Ig light chainOxalate Phenol Lambda-Ig light chainPseudouridine P-OHhippuric acid LeptinSymmetric dimethylarginine Quinolinic acid Methionine-enkepahlinUrea Spermidine Neuropeptide YUric acid Spermine Parathyroid hormoneXanthine Retinol binding protein*CMPF is carboxy-methyl-propyl-furanpropionic acid Tumor necrosis factor alpha

Vanholder R. et al New insights in uremic toxins. Kidney Int, 2003, 63; 84: S6–S10

Middle molecules

ββββ2 - Microglobulin

HDF vs Daily HDF, ß2-M Kinetic

Maduell F et al, Kidney Int. 2003; 64:3058 patients (6M, 2F)

4-5 hrs x 3 to 2-2,5 hrs x 6 per week for 6 months

Online HDF provides a platform for developing

new RRT options

Automated dialysis

procedure

CleansingPriming

Blood volumecontrolledmachine

Manual infusion

Flexible HDF

Priming

Rinsing

Suppressing saline

requirementReducing

manualhandling

Save money

Biofeedback system

infusion

Self Care or Home therapy

Internal HDF

If you want to know more register to

[email protected]

European Dialysis Working Group dedicated

to improve dialysis outcomes focusing on

online convective therapies

Documents

Hemodiafiltration: Where are we ? Where are we going · Hemodiafiltration: Where are we ? Where are we going ? Controversies conference on Novel techniques and innovation in blood