ASN DIALYSIS ADVISORY GROUP
ASN DIALYSIS CURRICULUM
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Hemodiafiltration
Martin K. Kuhlmann, MD
Vivantes Klinikum im Friedrichshain
Berlin, Germany
[email protected]
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Dialysis in ESRD: Problems with
conventional diffusive hemodialysis
-Excessive cardiovascular mortality
-Insufficient removal of middle molecules
-Insufficient removal of phosphate
-High risk of intradialytic hypotension
-Suboptimal dialysate quality
-Internal back-filtration with potential translocation of
bacterial DNA
-Chronic inflammation and protein-energy wasting
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Rationale for increasing the elimination of
higher molecular weight substances
-Direct vascular toxicity has been documented for a
number of uremic middle molecular size molecules
(EuTox-group)
-Higher circulating levels of middle molecules (such as
vitamin B12 or b2-microglobulin) in dialysis patients
are associated with cardiovascular and infectionrelated mortality in nonrandomized studies. (Liabeuf
S et al. Kidney Int 2012; 82: 1297)
-In the HEMO study secondary analysis revealed a
favorable effect of high-flux HD on the risk of death
and/or hospitalization due to cardiac causes.
(Eknoyan et al. New Eng J Med 2002; 347: 2010)
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Rationale 2: The effects of flux on clinical
outcome MPO-Study: High-flux vs. Low-flux
MPO-study:
Overall no clinical benefit of high-flux HD
was observed in this RCT. However,
diabetic patients and patients with base
line serum albumin levels < 4 g/L
benefitted significantly from high-flux HD
Locatelli F et al: JASN 20:645, 2009
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Removal of middle molecules is increased
by convective strategies
High-Flux Dialysis
HDF
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Convective dialysis therapies
Convective dialysis therapies clear water across the
dialysis membrane using positive transmembrane
pressure. Most middle molecules and phosphate are
dragged with water into the dialysate waste.
Convective modes of dialysis:
• High-flux HD
• Hemofiltration [HF]
• Hemodiafiltration [HDF]*
• Acetate-free biofiltration
* Note: HDF is not currently approved by the FDA in the US
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Basics of online-Hemodiafiltration
-In HDF, diffusive and convective dialysis modalities are
combined. Diffusion occurs along the transmembrane
concentration gradient between plasma and dialysate, while
convective transport is obtained by filtering, through a highflux dialyzer, amounts of plasma water considerably in excess
of those required to manage interdialytic weight gain.
-Fluid balance is maintained by simultaneously infusing online
generated sterile substitution fluid directly into the patient’s
bloodstream.
-Fluid can be substituted before (pre-dilution), within (middilution), or after the dialyzer (post-dilution).
-Clearance of middle- and large molecular-weight substances is
substantially greater during HDF than during high-flux HD.
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HDF: Middle molecule clearance is related to
ultrafiltration (UF) rate
convection
diffusion
clearance
urea
(ml/min)
(ml/min)
200
100
clearance
vitamin B12
10%
10%
clearance
inulin
(ml/min)
200
200
100
100
50%
50%
120%
120%
0
60 90 UF rate
30
0
(ml/min)
Calculated values
0
0
30
60
90
0
UF rate 0
(ml/min)
30
60
Adapted from Ledebo I, Blankestijn PJ; NDT Plus 2010; 3:8
90 UF rate
(ml/min)
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On-line HDF allows significant higher UF rates
than high-flux HD and classical HDF
High-flux HD
with 10-20 ml/min
ultrafiltration rate
510
300
blood
ultrapure
dialysis
fluid
Classical HDF
On-line HDF
with 50 ml/min
ultrafiltration rate
with 90 ml/min
ultrafiltration rate
300
300
blood
500
550
ultrapure
dialysis
fluid
blood
ultrapure
dialysis
fluid
420
500
40
290 ml/min
510
290
substitution
fluid from bags
Filter
290
500
80
online generated, sterile
substitution fluid
Adapted from Ledebo I, Blankestijn; PJ NDT Plus 2010; 3:8
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Basics of online-HDF: Dosing
-Generally, Dialysis dose can be defined as the net product of
‘solute clearance’ (K) and ‘treatment time’ (t)
-In HDF, solute clearance ‘K’ is determined by total convective
volume (CV, Liters) achieved during treatment
-‘CV’ is governed by ultrafiltration rate (UFR, ml/min) and treatment
time (t)
-‘UFR’ = substitution rate + water removal required to achieve target
weight
-‘UFR’ is determined by blood flow rate (Qb, ml/min) and filtration
fraction (FF, ml/min)
-‘FF’ is the fraction of plasma water filtered during passage of blood
through the dialyzer
-Blood is thickening during filtration; to prevent filter clotting, ‘FF’
should not exceed 30 % of ‘Qb’
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HDF dosing: clinical example
Prescription:
Target convective volume (CV): 24 L per treatment
Treatment time (t): 240 min
Blood flow rate (Qb): 400 ml/min
Then:
Ultrafiltration rate (UFR) = CV/t = 100 ml/min
Filtration fraction = UFR/Qb = 100/400 = 25 % of Qb
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Online-HDF: Expectations based on
small, non-randomized clinical studies
Increased removal of middle molecules
Higher removal of phosphate
Better intradialytic hemodynamic stability
Less inflammation due to sterile dialysate
Lower infection rates
Improved appetite
Better quality of life
Improved cardiovascular outcome
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Most relevant clinical studies and
meta-analyses on mortality outcome
Observational studies
• DOPPS (Canaud B et al. Kidney Int 2006; 69:2087
Randomized controlled studies
• Dutch Study (CONTRAST; Grooteman MPC et al. JASN 2012; 23:
1087)
• Turkish Study (Ok E et al. Nephrol Dial Transplant 2013; 28: 192)
• Spanish Study (ESHOL; Maduell F et al. JASN 2013; 24: 487)
Meta-analyses
• Wang F et al. Am J Kidney Dis 2014; 63: 968
• Susantitaphong et al. Nephrol Dial Transplant 2013; 28: 2859
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DOPPS shows survival advantage for pts on highefficiency HDF (convective volume > 15 L per Tx)
CV > 15 L/Tx
Canaud B et al. KI 2006; 69:2087
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RCTs: Dutch HDF study
CONvective TRAnsport STudy (CONTRAST)
Idea
Design
Study sites
Duration
Population
Groups
Treatment
Investigator initiated, multicenter trial
Prospective, randomised, controlled, event-driven
29 Dialysis centers (26 NL, 2 CA, 1 NOR)
01/2004 – 12/2010
714 prevalent HD-Pts. > 18 years on low-flux-HD
Online-HDF (358) vs. low-flux HD (356)
post-dilution ol-HDF, target UFR 6 L/h = 24 L/Tx
minimum-Kt/V: 1.2; fixed treatment time
ultra-pure dialysate for ol-HDF and HD
1° outcome
2° outcome
All-cause mortality (target: 250 events in 3 years)
Composite of fatal and non-fatal cv events
Grooteman MPC et al. JASN 2012; 23:1087
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CONTRAST study: Primary Outcome
All-cause mortality
Cardiovascular events
Grooteman MPC et al. JASN 2012; 23:1087
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CONTRAST subanalysis: Achieved convective
volume > 22 L associates with better outcome
Grooteman MPC et al. JASN 2012; 23:1087
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CONTRAST: Further results
Online-HDF had no significant effects on indicators of
cardiovascular mortality risk, such as ‚left ventricular
mass‘, ‚ejection fraction‘ and ‚pulse wave velocity‘
(Mostovaya IM et al. CJASN 2014; 9: 520)
Compared to low-flux HD with ultrapure dialysis fluid,
treatment with online-HDF did not result in a decrease in
ESA resistance. (Van der Weert NC et al. PLoS ONE 2014;
9(4): e94434)
Online-HDF with ultrapure dialysate seems to reduce
inflammatory activity over time compared to low-flux HD,
but does not affect the rate of change in albumin. (Den
Hoedt CH et al. Kidney Int. 2014;)
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RCTs: Turkish online-HDF-Study
Study sites
Duration
Population
Groups
Treatment
10 Fresenius dialysis centers
01/2007 – 04/2010
782 prevalent HD-Pts. > 18 years on high-flux-HD
Online-HDF (391) vs. high-flux HD (391)
post-dilution ol-HDF, target UFR > 15 L/Tx
minimum-Kt/V: 1.2; treatment time 240 min
ultra-pure dialysate for ol-HDF and HD
1° outcome All-cause mortality,
first non-fatal cardiovascular event
2° outcome Cardiovascular mortality,
hospitalization rate,
intradialytic complications
Ok E. et al. NDT 2013; 28:192-202
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Turkish online-HDF-Study: Results
The composite of all-cause mortality and nonfatal
cardiovascular event rate was not different in the olHDF and in the high-flux HD groups.
In a post-hoc analysis, ol-HDF treatment with
substitution volumes > 17.4 L per treatment was
associated with better cardiovascular and overall
survival.
Comment: The Turkish ol-HDF study, like the CONTRAST study,
reports a dose-effect relation between achieved convective
volume and mortality risk.
Ok E. et al. NDT 2013; 28:192-202
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RCTs: The Spanish HDF study
Maduell F. et al. JASN 2013; 24:487-497
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ESHOL study: Primary Outcome
High-volume ol-HDF superior to high-flux HD
Maduell F. et al. JASN 2013; 24:487-497
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ESHOL: Summary of 1°and 2°outcomes
30% reduction of overall mortality
33% reduction of cardiovascular mortality
61% reduction of stroke mortality
55% reduction of infection associated mortality
28% reduction of intradialytic hypotension
22% reduction of hospitalisation
Maduell F. et al. JASN 2013; 24:487-497
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ESHOL: Dose-effect relation
Maduell F. et al. JASN 2013; 24:487-497
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ESHOL: Summary and interpretation
-This is the first study to show that high-efficiency
postdilution ol-HDF reduces all-cause mortality
compared with conventional HD
-Target CV was 18 L/Tx; mean achieved CV was higher
than in the other two studies; however, acc. to
protocol, patients not reaching the target CV for > 2
consecutive months were withdrawn from the study
and also from study analysis. (Comment: this causes
a selection bias and is a major criticism of the study)
-The study also demonstrates a significant dose-effect
relation, similar to the Dutch and the Turkish HDFstudies
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Meta-analysis:
Convective vs. diffusive dialysis modalities
Convective therapy
Hemofiltration (n=274)
High-flux HD (n=3,204)
Hemodiafiltration (n=1,288)
Duration of follow-up
7-12 months (n=377)
>12 months (n=4,389)
Study Quality
Fair (n=452)
Good (n=4,314)
Susantitaphong et al. NDT 2013; 28: 2859
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Meta-analysis: HDF vs. HD
All-cause and cardiovascular mortality
Cardiovascular outcomes
HDF
Schiffl (2007)
OK (2011)
Grotteman (2012)
Maduell (2013)
Overall (I2=41.7%, p=0.16)
All-cause mortality
HDF
Locatelli (1996)
Wizemann (2001)
Schiffl (2007)
OK (2011)
Grotteman (2012)
Maduell (2013)
Subtotal (I2=58.6%, p=0.03)
HF
Beerenhout (2005)
Santoro (2008)
Alvestrand (2011)
Subtotal (I2=0.0%, p=0.54)
HDF or HF
Locatelli (2010)
Subtotal (I2=.., p=.)
Overall (I2=38.3%, p=0.10)
Wang AY et al. AJKD 2014; 63:968-978
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Meta-analysis: HDF vs. HD
Symptomatic intradialytic hypotension
Symptomatic Hypotension
HDF
Lin (2001)
Schiffl (2007)
Maduell (2013)
Subtotal (I2=86.1%, p=0.001)
HF
Santoro (2008)
Subtotal
HDF or HF
Locatelli (2010)
Subtotal
Overall (I2=76.7%, p=0.002)
Wang AY et al. AJKD 2014; 63:968-978
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Online-HDF: Safety of online generated
sterile replacement fluid
None of the three RCTs were specifically designed to
examine safety issues
None of the three RCTs provided any indication that HDF is
an unsafe treatment modality
CONTRAST data indicate that substitution fluid of adequate
quality can be produced online over a prolonged period
of time
In ESHOL, mortality risk from infectious causes was
significantly lower among ol-HDF pts. vs. HD pts.
Inflammation markers did not differ between ol-HDF and HD
in any of the three trials
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online-HDF: Conclusion
-ol-HDF may increase removal of middle molecules and phosphate; however,
no clincial trial has shown an effect of HDF on blood levels of commonly
measured middle molecules
-Both, CONTRAST and the Turkish HDF study did not show survival benefits
for HDF vs. conventional HD. In post-hoc analysis survival benefits for pts
treated with high volume ol-HDF (CV > 17.5 – 22 L/Tx) were observed in
both trials
-ESHOL demonstrates better outcomes for high-volume ol-HDF (CV > 22 L/Tx)
vs. high-flux HD including a dose-effect relation
-Two meta-analyses were unable to show significant survival benefits for olHDF vs. conventional HD; Further studies will be required to test the
hypothesis that high-volume HDF is superior to high-flux HD
-An individual patient data meta-analysis of all ol-HDF RCTs is currently being
conducted to examine the effects of body size-adjusted HDF-dosing on
outcome.
-ol-HDF is safe with no increased risk for infection and associates with
increased hemodynamic stability; ol-HDF may be slightly more costly than
HD (+ 3%)
-Current recommendations for HDF-dosing include an achieved CV > 22 L/Tx