Online Hemodiafiltration:
Renal Replacement Therapy
of the Future Available Today
Prof. Bernard Canaud
Néphrologie, Dialyse et Soins Intensifs
Hôpital Lapeyronie – CHRU Montpellier
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Mitka M. JAMA, 2002; 287(20): 2643-2644
After the HEMO Study !!!
Dialysis and CKD-related pathology
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Hemodiafiltration mimics the “native nephron”
Inlet
arteriole
Outlet
arteriole
Glomerulus
Glomerular
Chamber
Capillary
Network
Renal
Vein
1. Filtration
2. Reabsorption
3. Secretion
4. Excretion
Substitution
Fluid (SF)
Ultrafilter
Inlet Blood Flow
100
Outlet Blood Flow
Outlet D+UF
Inlet D+SF
1. Ultrafiltration
2. Diffusion
3. Adsorption1
2
2
3
Factors affecting HDF efficacy
• Hemodiafilter characteristics
• Blood flow – Dialysate flow
• Site of infusion for substitution
• Flow and/or volume of substitution
• Weight loss - Ultrafiltration
• Dialysate composition
• Duration of HDF session
• Weekly frequency of sessions
• Patient’s characteristic
• Treatment schedule
– 3 sessions of 4 hours weekly (minimum)
• Highly permeable synthetic membrane
• Large surface area > 1.8 m2
• Ultrapure bicarbonate dialysis fluid
• High blood flow (effective QB: 350 - 400 ml/min)
• High dialysate flow diffusive dose
– Optimize 500-700 ml/min
• Large volume of substitution convective dose
– Post-dilution (Qsub : 100 ml/min, 24 l / session)
– Pre-dilution (Qsub : 200 ml/min, 48 l / session)
Standard prescription for high-efficiency on-line
HDF
On-line HDF, post-dilution mode
Substitution
fluid
Ultrafiltrate
(Fluid balance)
Ultra
pu
re
dia
lys
is flu
id
Ultrafilter
Blo
od
Flo
w
800
100
810
700
700
110400
390
Ultrafiltrate
(Weight loss)
On-line HDF, pre-dilution mode
Substitution
fluidU
ltrap
ure
dia
lysis
fluid
Ultrafilter
Blo
od
Flo
w
800
810
800
600
200
400
390
210
UF
UF
On-line HDF, mixed-dilution mode
Substitution
fluidU
ltrap
ure
dia
lysis
fluid
Ultrafilters
Blo
od
Flo
w
800
810
700
650
50
400
390
160
UF
UF
100
On-line HDF, mid-dilution mode
400 390
Ultra
pu
re
dia
lys
is flu
id
Blood
Flow
Ultrafilters
UF
UF
810
650
800
150
Substitution
fluid
Mid-Reverse
Ultrafilters150
UF
UF
400 390
Blood
Flow
810
800650
Ultra
pu
re
dia
lysis
fluid
Mid-Double Reverse
PR 2-Microglobulin, %
Convective dose is a linear function of
substitution volume in post-dilution HDF
Lornoy W et al, Nephrol Dial Transplant. 2000: 15: 49-54
Post-dilution HDF increases removal of
middle molecules
Maduell F et al, Am J Kidney Dis 2002; 40:582
60D 113D 5.8kD 11.8kD 17.2kD
Matching dialysis dose in pre vs post HDF
Canaud B et al, Blood Purif. 2004; 22:40-48
RCT Cross-Over Study
8 HD patients 4h x 3 wk
Qb 400 Qd 800 Qinf 100/200
Matching efficacy pre vs post-dilution HDF
requires double substitution flow
Canaud B et al, Blood Purif. 2004; 22:40-48
Qinf 100ml/min (24 l/ses)
Qinf 200ml/min (48 l/ses)
RCT Cross-Over Study
8 HD patients 4h x 3 wk
Qb 400 Qd 800 Qinf 100/200
20pts – Mid-dilution HDF Ol-PUR190
tHDF 275mn - Qb 450ml/mn - Qd 800ml/mn Maduell F et al, Blood Purif. 2010; 30:25–33
Optimal flow substitution in mid-dilution HDF
80,782,7 82,4
84,9 84 84,8 84
69,9
72,9 72,3
77,4 7778,2
79,6
50
55
60
65
70
75
80
85
90
95
100
Mid 0 Mid 50 Mid 100 Mid 150 Mid 200 Mid 250 Mid 300
PR ß2-M
PR-Myog
Percent reduction per session, %
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Factors affecting safety of online HDF
• Hemodiafiltration machine
• Ultrapurity of water feeding HDF machines
• Cold sterilization of dialysis fluid by ultrafilter
• Hygienic handling of water and HDF machines
• Microbiological monitoring of dialysis fluid
• Periodical change of ultrafilters
Fresenius
5008
Nikkiso
DBB-5
B.Braun
Dialog+
Fresenius
4008 Gambr
o
AK200
S
Gambro
Innova
Bellco
Formula2000
Certified online hemodiafiltration machines
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
• 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
• 11258 HDF sessions
• No febrile reactions
• No clinical adverse events
Penne EL et al, Kidney Int. 2009 ; 76: 665-672CONTRAST Dutch Convective Transport Study
Water treatment system mainly used
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-up
11258 HDF sessions
97 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
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Long term studiesShort term studies
Biological and clinical effects of HDF
Biological effects
• Enhance solute transfer
– Enhances low and middle
molecule removal
– Enhances solute and electrolyte
mass transfer
• Reduce blood/dialysis interaction
– Reduces protein and cells
activation
– Reduces micro-inflammation
Clinical effects
• Morbidity
– Reduces intradialytic hypotension
– Prevents 2M-amyloidosis
– Improves nutritional state
– Facilitates anemia correction
• Mortality
– Reduces overall mortality
– Reduces cardiovascular events
Long term studiesShort term studies
Biological and clinical impact of HDF
Biological impact
• Enhance solute transfer
– Enhances low and middle
molecule removal
– Enhances solute and electrolyte
mass transfer
• Reduce blood/dialysis interaction
– Reduces protein and cells
activation
– Reduces micro-inflammation
Clinical impact
• Morbidity
– Reduces intradialytic hypotension
– Prevents 2M-amyloidosis
– Improves nutritional state
– Facilitates anemia correction
• Mortality
– Reduces overall mortality
– Reduces cardiovascular events
HDF vs LF-HD, Impact on circulating ß2-M
concentrations
Wizemann V et al, Nephrol Dial Transplant 2000; 15: 43
ß2-M concentrations is reduced after
switching from HFHD to ol-HDF
Tiranathanagul K et al. Ther Apher Dial 2009; 13: 56-62
Comparison of percent reduction of solutes
mid-dilution vs post-dilution
Krieter DH et al, Kidney Int, 2005; 67: 349-356
10 HD pats
Randomized cross-over study
1 week Mid-dil ol-Pur190 vs Post-dil HF80
ß2-Microglobulin concentrations tend to be
lower with Mid-HDF
Krieter DH et al, Kidney Int, 2005; 67: 349-356
10 HD pats
Randomized cross-over study
1 week Mid-dil ol-Pur190 vs Post-dil HF80
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 - QD800
Direct dialysate quantification
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
Effects of oL-HDF and HFR on inflammatory and nutritional markers
Panichi V et al, Nephrol Dial Transplant 2006; 21: 756-762
Cross-over, randomized multicentre trial
25 HD patients
Effects of oL-HDF and HFR on inflammatory and nutritional markers
Cross-over, randomized multicentre trial
Panichi V et al, Nephrol Dial Transplant 2006; 21: 756-762
CD14+ CD16+
TNF- IL6
Telomere length
HF-HD OL-HDF HF-HD OL-HDF HFHD
4 months 4 months 4 months 4 months4 months
• Polysulfone membrane
• Ultrapure dialysate
• Same dialysis conditions
Effect of HD and HDF on CD14+CD16+ monocytes, TNF, IL6 and inflammatory markers
Cross-over, randomized study (31 HD patients)
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
Comparison of different RRT modalities on inflammation and survival of HD patients
Panichi V et al. Nephrol Dial Transplant. 2008; 23:2337-2343 RISCAVID Study
• Prospective observational study
• Prevalent HD patients (Tuscany, Italy) (70±76 months)
• 757 HD patients (age 66±14)
• Stratified at start in 3 RRT groups: BHD, bag-HDF, ol-HDF
• Prospective follow-up for 30 months
757 HDprevalent patients
BHD-HF 424pts
Bag-HDF 204pts
ol-HDF 129pts High Efficiency HDF 23±3l/s
Low Efficiency HDF 14±3l/s
30 months
Demographic data at start of study period
Panichi V et al. Nephrol Dial Transplant. 2008; 23:2337-2343 RISCAVID Study
Effects on chronic inflammation
Panichi V et al. Nephrol Dial Transplant. 2008; 23:2337-2343 RISCAVID Study
Long term studiesShort term studies
Biological and clinical impact of HDF
Biological impact
• Enhance solute transfer
– Enhances low and middle molecule
removal
– Enhances solute and electrolyte
mass transfer
• Reduce blood/dialysis interaction
– Reduces protein and cells activation
– Reduces micro-inflammation
Clinical impact
• Morbidity
– Reduces intradialytic hypotension
– Prevents 2M-amyloidosis
– Improves nutritional state
– Facilitates anemia correction
• Mortality
– Reduces overall mortality
– Reduces cardiovascular events
Hemodynamic 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)
Locatelli F et al, J Am Soc Nephrol 2010; 21:1798-1807Italian Multicentric Study RCT
LFHD, HF, HDF Ratio 2/1/1
Total incidence of ISH 7.5% 28950 sessions
9.8 to 8.0%
18.4%
10.6 to 5.2%
50.9%
7.1 to 7.9%
9.9%
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 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
On-line HDF versus low flux HD, prospective
randomized study
Wizemann V et al, Nephrol Dial Transplant. 2000; 15: 43-48
LFHD
HDF
LFHD
44 pats
21 pats
23 pats 15 pats
16 pats
24 months
3 months
On-line HDF versus low flux HD, Mortality
Wizemann V et al, Nephrol Dial Transplant. 2000; 15: 43-48
LFHD
HDF
LFHD
44 pats
2 Deaths3 Transfer
1 Death2 TPL4 Transfer1 Fever
21 pats
23 pats 15 pats
16 pats
24 months
3 months
Mortality
2/21
9,5%
1/23
4,3%
Prospective randomized cross-over long-term comparison of on-line HDF vs HFHD
Schiffl H, Eur J Med Res. 2007; 12(1): 26-33
LFHD
76 pats24 months 24 months
UPHD HDF38 35 35 31
HDF UPHD38 34 34 30
Prospective randomized cross-over long-term comparison of on-line HDF vs HFHD
Schiffl H, Eur J Med Res. 2007; 12(1):26-33
HDF UPHD
2 Death (CVE)
2 TPL
2 Death (MI)
2 TPL
38 34 34 303/72
4,16%
UPHD HDF38 35 35 31
1 Death (MI)
1 TPL
1 Transfer
1 Death (MI)
2 TPL
1 TransferMortality
3/73
4,11%
LFHD
76 pats24 months 24 months 48 months
Canaud B et al, Kidney Int 2006; 69: 2087-2093
Distribution of dialysis modality for prevalent patients
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
Crude mortality of CKD patients according to their treatment
modality HD vs HDF
De
ath
s, (%
)
7%
Euclid, FMC Jirka et al, Kidney Int 2006; 70:1524
Euclid56 clinics
2564 pats
HD2170, HDF394
4 countries
Relative risk of mortality in CKD patientsHDF versus HD
1,05
1,578
1,458
1,36
1,653
1,036
1,642
0,636
0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8
Age
Diabetes
Neoplasia
Heart Fail
Arteriopathy
Time on RRT
Treat time >240
OL-HDF 36,4%
Euclid, FMC Jirka et al, Kidney Int 2006; 70:1524
Retrospective analysis of cohort, HF-HD versus HDF
HFHD
161 pats
HDF
168 pats
Sep 2003 Dec 2006Apr 2006
Demographic
Comorbidity
Dialysis efficacy indicators
Crude mortality
RR mortality (all-causes)
RR morbidity (hospitalization)
115 pats
Vinhas Josè et al, Port J Nephrol Hypertension 2007; 21 (4): 287-292
Crude mortality, death/100 patient-years
Sep 2003 Dec 2006Apr 2006
Crude
Mortality
HFHD
161 pats
HDF
168 pats
Vinhas Josè et al, Port J Nephrol Hypertension 2007; 21 (4): 287-292
Cause of death in CKD, repartition by modality
10,9
3,6
12,7
3,6
10,9
7,3
1,8
12,7
0
36,4
0
10
20
30
40
50
Cardiac Infection Neoplasia Malnutrition Others
HFHD
HDF
% of total death
Vinhas Josè et al, Port J Nephrol Hypertension 2007; 21 (4): 287-292
Cardiovascular mortality is reduced in ol-HDF
Panichi V et al. Nephrol Dial Transplant. 2008; 23:2337-2343 RISCAVID Study
Categorical and continuous variables distribution
according to ERI values categorized into four quartiles
Panichi V et al, Nephrol Dial Transplant 2011 ePub
QI <5.6 Q I 5.7-9.6 QIII 9.4-15.4 QV >15.4
RISCAVID Study
Panichi V et al, Nephrol Dial Transplant 2011 ePub
Survival (all causes mortality) of dialysis
patients stratified by ERI
Q I <5.6
Q II 5.7-9.6
Q III 9.4-15.4
Q IV >15.4
RISCAVID Study
Effect of on-line high-flux hemofiltration versus
low flux hemodialysis in CKD
Santoro A et al, Am J Kidney Dis. 2008; 52: 507-512
Survival is improved in high efficiency HF
Santoro A et al, Am J Kidney Dis. 2008; 52: 507-512
≈ +20%
Convective dialysis dose and ß-2 Microglobulin
levels seem to play a major role in this positive effect
Santoro A et al, Am J Kidney Dis. 2008; 52: 507-512
Long-term outcomes in ol-HDF vs HFHD, a
comparative analysis
Vilar E et al, Clin J Am Soc Nephrol 2009, ePub
Repartition according to time spent on HD
vs HDF
Vilar E et al, Clin J Am Soc Nephrol 2009, ePub
Survival is improved in patients who
predominantly received HDF
Vilar E et al, Clin J Am Soc Nephrol 2009, ePub
RR 0.66 vs 1.0 for HDF
Life gain
+34%
Outcomes of HDF versus HD
Author, Year HDF vs Comparator Type of study 2-M Survival
Wizemann V et al, 2000 HDF vs LFHD RCT =
Bosch JP et al, 2006HDF vs LFHD vs
HFHDHistorical prospective
cohort? 45%
Canaud B et al 2006HDF+/- vs LFHD vs
HFHDHistorical prospective
cohort? 35%
Jirka et al, 2006HDF vs LFHD vs
HFHDHistorical prospective
cohort? 36%
Schiffl H et al, 2007HDF vs HFHD
+ UPDRCT =
Vinhas J et al, 2007 HDF vs HFHD Prospective controlled study ? 50%
Panichi V et al. 2008 HDF+/- vs LFHD Prospective controlled study 15%
Santoro A et al, 2008 HF vs HFHD RCT 18%
Tiranathanagul K 2009 HDF vs HFHD Prospective controlled study =
Vilar E et al, 2009 HDF vs HFHDHistorical prospective
cohort 34%
Locatelli F et al, 2010 HDF vs HD vs LFHDProspective randomized
controlled study? =
Daily online HDF promotes catch-up
growth in CKD children
Fischbach M et al, Nephrol Dial Transplant. 2009;
Typical example of
growth catch-up !
Outline of the presentation
• Concerns related to renal replacement therapy
• Technical aspects of online HDF
• Safety of online HDF
• Efficacy of online HDF
– Biological effects
– Clinical effects• Clinical tolerance
• Morbidity and Mortality
• Take home message
Randomized clinical trials in Europe
evaluating HDF vs HD
Dutch Trial
CONTRAST
LFHD vs HDF
350/350
CV events
Mortality
36 months
French Trial
HFHD vs HDF
> 65yo
300/300
Tolerance
CV events
Mortality
24 months
Catalonian Trial
HFHD vs HDF
300/300
CV events
Mortality
24 months
Turkish Trial
HFHD vs HDF
300/300
CV events
Mortality
24 months
Italian Trial
LFHD vs HF/HDF
150/75/75
Tolerance
Morbidity
Mortality
24 months
Enrolment period of all these studies is closed
Take home message
• Online hemodiafiltration is
– Safe,
– Very effective,
– Economically affordable,
– Improving session tolerance,
– Not inferior to high flux hemodialysis
– Superior to high flux hemodialysis ( ? RCT)
Potts M et al, BMJ 2006; 333:701-703
Sometimes it’s best just to jump in !
Why not using online hemodiafiltration ?
Potts M et al, BMJ 2006; 333:701-703
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