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
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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†
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
Penne EL et al, Kidney Int. 2009 ; 76: 665-672CONTRAST Dutch Convective Transport Study
Ultrapurity of dialysis fluid is confirmed in
85 to 98% of samples
10 centers
One year follow-up11258 HDF sessions97 patients – 3961 samples
Penne EL et al, Kidney Int. 2009 ; 76: 665-672CONTRAST Dutch Convective Transport Study
Ultrapurity of infusate is confirmed in 99 to
100 % of samples
Penne EL et al, Kidney Int. 2009 ; 76: 665-672CONTRAST Dutch Convective Transport Study
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
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
Maduell F et al, Nephro Dial Transplant. 2011; 0:1-13 ePub 13Sep2011
Considerable reduction of phosphate binders
consumption
Maduell F et al, Nephro Dial Transplant. 2011; 0:1-13 ePub 13Sep2011
Significant beneficial effect on nutritional
status
Maduell F et al, Nephro Dial Transplant. 2011; 0:1-13 ePub 13Sep2011
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
Historical prospective cohort
? 12.7/8.9 ���� 35%
Jirka et al, 2006 HDF vs LFHD vsHFHD
Historical prospective cohort
? 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
Outline of the presentation
DefinitionDefinition
EpidemioEpidemioFutureFutureof HDFof HDF
RegulatoryRegulatory
SafetySafetyEfficacyEfficacy
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
European Dialysis Working Group dedicated
to improve dialysis outcomes focusing on
online convective therapies
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