online hemodiafiltration: renal replacement therapy of the

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

Mitka M. JAMA, 2002; 287(20): 2643-2644

After the HEMO Study !!!

Dialysis and CKD-related pathology

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, %

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


Water treatment system mainly used


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


Ultrapurity of infusate is confirmed in

99 to 100 % of samples


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


Biological and clinical impact of HDF

Biological impact


– Enhances low and middle

molecule removal


mass transfer


– Reduces protein and cells

activation


Clinical impact

• Morbidity





• Mortality



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


Effects on chronic inflammation



Biological and clinical impact of HDF

Biological impact


– Enhances low and middle molecule

removal


mass transfer


– Reduces protein and cells activation


Clinical impact

• Morbidity





• Mortality



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


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


Cardiovascular mortality is reduced in ol-HDF


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


≈ +20%

Convective dialysis dose and ß-2 Microglobulin

levels seem to play a major role in this positive effect


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


Survival is improved in patients who

predominantly received HDF


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


cohort? 35%

Jirka et al, 2006HDF vs LFHD vs


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 !

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

online hemodiafiltration: renal replacement therapy of the

Documents