Hemodialysis vs. Hemodiafiltration
Hemodialysis Symposium
8-9 February, 2014
Al-Madinah Al-Munawwarah, KSA
Saad Alobaili
KKUH, KSU
Riyadh
Classification
Small molecules
e.g. urea (60), creatinine (113), phosphate
(134)
Middle molecules
e.g. vitamin B12 (1355), vancomycin (1448),
inulin *5200, endotoxin fragments (100015,000) parathormone (9425),
ß2-m (11,818)
Large molecules
e.g. myoglobulin (17,000), RBP (21,000), α 1m (26,700), EPO (30,000), albumin (66,000),
transferrin (90,000)
Molecular weight range
< 500
500 – 15,000
> 15,000
Main Uremic Toxins
3 Mechanisms of solute removal
1- Diffusion: Solute removal according to concentration
difference between plasma water and the dialysate.




Is greatest for small molecules removal
Small molecules have better access to the membrane
Increase with increasing the small solute conce. gradient
Membrane factors: Sieving coefficient, porosity of the
membrane, diffusivity & thickness of the membrane
 Decreases with increasing molecular size of a solute
Basic Principles of solute removal
2- Convection: solute clearance occurs as a result of
water flow through the membrane in response to
hydrostatic pressure difference between the two sides
of the membrane.
(solvent drag).
 The driving force is a pressure gradient rather than a
concentration gradient
 The major impact comes from the solute size relative to the
membrane pores size (radius)
 Iis determined exclusively by the sieving properties of the
membrane, S=1 for Water
 Is more important for solute removal as the molecular size of
the solute increases.
 Serves 2 purposes: water and solute removal along.
Basic Principles of solute removal
3- Adsorption: Plasma proteins being adsorbed to the
surface of the membrane. ( So, effect is limited to LMW
Proteins clearance)
 Difficult t estimate
 High flux membranes has more protein adsorption than Low
Flux membranes ( Larger pores)
 Ay decrease the Diffusive & Convective transport of LMW
proteins.
I. Ledebo and P. J. Blankestijn, NDT plus 2010
Determinants of Convective Transport Across
Membranes:
•
•
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•
•
•
•
Water flux across the membrane
Pore size and pore size distribution of the membrane
Molecular size (molecular mass)
Hydrostatic pressure difference
Viscosity of the fluid in the membrane pores
Molecular shape and configuration
Charges (solutes and membranes)
Important Dialyzer character relevant to its
Convective function:
Ucoeff or KUF:
( mL/h/mm Hg)
It characterizes the membrane’s permeability to water.
The higher Ucoeff is, the greater the permeability to water
The higher Ucoeff is, the greater contribution of CONVECTION
(solvent drag) to solute removal (middle molecules)
Dialyzers are classified as:
Ucoeff
(ml/h/mm Hg)
Conventional
≤ 12
High-flux
> 14
β2-Microglobulin
Clearance
( mL/min)
≤ 10
( > 40 )
>20
- Some refer to “FLUX” as ability to remove ß2-M.
- High-Flux dialyzers: are considered convective dialyzers ( Filtration and
back filtration of 6-8 L over 4 hs conventional HD session.
Ledebo I. Principles and practice of hemofiltration and hemodiafiltration.Artif Organs 1998; 22: 20–25
Both the Hemodialysis (HEMO) study and the Membrane
Permeability Outcome (MPO) study compared low-fl ux
hemodialysis with high-fl ux hemodialysis. Neither study
showed a difference in mortality risk between the treatment
arms.
In HEMO, High-flux HD was associated with an 8% nonsignificant reduction of mortality compared with low-flux HD
Secondary analyses in the HEMO and MPO studies suggested a
survival benefit of high-flux hemodialysis in patients with a
dialysis vintage >3.7 years, patients with diabetes, and if serum
albumin < 40 g/L at baseline.
Uremic solutes with known negative impact on the cell systems involved in
atherogenesis and the clinical development of cardiovascular and
cerebrovascular problems, CV mortality rate is still 10 times higher than in the
general population
J Am Soc Nephrol 9[Suppl]: S16–S23, 1998
Vanholder et alThe International Journal of Artificial Organs / Vol. 24 / no. 10, 2001
Normal β2 microglobulin level: 1-2 mg/L
Targeted in HD population 15-20 mg/L
RISCAVID
Prospective study of 757 HD patients, followed for 30
months
• HD (n = 424)
• Haemodiafiltration with sterile bags (n = 204)
• online HDF (n = 129)
RISCAVID
• All-cause and CV mortality was 12.9%/year(HD) and
5.9%/year(HDF)
• CRP and pro-inflammatory cytokines showed an increased risk
for CV (RR 1.9, P < 0.001) and all-cause mortality (RR 2.57, P <
0.001)
• HDF patients had a significantly increased adjusted cumulative
survival than BHD (P < 0.01)
Conventional HD=
Diffusion + convection (UF) for excess fluid removal
+ convective clearance LMW (if high flux)
If Convective clearance is augmented (large convective volume
applied) for the sake of improving LMW proteins clearance:
Diffusion + Convection ( LMW P. removal) +
UF (excess fluid removal) = Hemodiafiltration (HDF)
HDF is a blood purification therapy combing diffusive and convective
solute transport using high -flux membranes characterized by an
ultrafiltration coefficient > 20 ml/h/mm Hg/m² and a sieving coefficient
for ß2- microglobulin greater than 0.6
Convective transport is achieved by an effective convection volume of at
least 20 % of the total blood volume processed.
Appropriate fluid balance is maintained by external infusion of an
ultrapure, non -pyrogenic solution into the patient`s blood.
Hemodiafiltration; beside the ongoing diffusive
therapy in the HD part, it relies on a large convective
volume requiring substitution fluid equal to the
convicted volume.
(e.g. 15 Ls to be convicted over 4hs in an HDF session
then it has to be replaced simultaneously with another
15 Ls of Ultra-pure water based substitution solution)
Advantages of HDF:
• Enhanced small, middle and larger m removal
• Protein-bound uremic solute clearance
• Better intradialytic hemodynamic stability
• Reduced inflammation & infection
• Anemia correction
• Improved phosphate control
• Improved CV status
Reduction ratio of B2M per session was 20–30% higher with
on-line HDF than with high-flux HD (72.7 versus 49.7%)
Nephrol Dial Transplant 2000; 15(Suppl 1)
Carpal tunnel syndrome surgery: 42% lower in patients
treated with HDF compared with those treated with HD
Kidney Int 1999; 55: 286–293
On-line HDF permits a similar reduction rate of small solutes
per session as that of HD: 70–80% for urea (60 daltons (da)
Nephrol Dial Transplant 2005; 20: 155–160
The substitution Fluid source:
1- Sterile fluid in pre-filed bags from a manufacturer.
OR
2- On site prepared solution ( same as dialysate)
(water from the RO further treated inside the HDF
machine)
Hence called On-Line HDF.
Substitution Fluid Preparation steps:
ANSI /AAMI/ ISO
ERA-EDTA guidelines
Water for dialysis
Bacteria (CFU/ml)
<100 (action level at 50)
<100
Endotoxin (EU/ml)
<0.5
<0.25
Bacteria (CFU/ml)
<100 (action level at 50)
<100
Endotoxin (EU/ml)
<0.5
<0.25
Ultrapure dialysate
Bacteria (CFU/ml)
Endotoxin (EU/ml)
<0.1
<0.03
<0.1
<0.03
Substitution fluid for infusion
Bacteria (CFU/ml)
Endotoxin (EU/ml)
Sterile
Undetectable
<10−6
<0.03
Dialysate
Procedure Pre-requisites:
1- Appropriate HDF machine (2 pumps: blood+
Replacement solution)
2- High-Flux dialyzer compatible with HDF mode.
3- High quality Dialysate & Substitution fluid(Ultra-pure)
4- Adequate V. access flow
5- Larger gauge HD needle
6- Trained staff
7- Health authority approval
Achieving higher convection
volumes
• Higher Qb
• Higher serum albumin
• Lower hematocrit
high haemoglobin and low albumin may attenuate
convection by reducing filtration fraction
Postdilution On-Line HDF
Best removal of small and
middle size uremic toxins –
filtration from undiluted
blood!
blood (out)
Substituate
(post)
But …
ultrafiltration limited by
HDF pump
Filtrate
(UF + HDF)
blood pump
blood (in)
Substitution solution enters
extrakorporal circuit after
dialyzer
• haemoconcentration
• high blood viscosity
• secondary protein layer
• membrane polarization
and high blood flow rates are
needed
The filtration rate should be limited to 40% of
plasma water flow rate, corresponding
to 25% of blood flow rate. EBPGD 2007
Predilution On-Line HDF
blood (out)
Improved membrane
permeability
- filtration from diluted
blood!
Filtrate
(UF + HDF)
HDF pump
blood pump
Substituate
(pre)
blood (in)
Substitution solution enters
extracorporeal circuit before
dialyser
But …
dilution also reduces
efficiency
• lower diffusion gradient
• reduced clearance for
small molecules
2010-2011
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0.7% in Finland
18.9% in the Catalonian (Spain)
21.5% Australia
10.9% New Zealand
>60 % Switzerland, Slovenia
55% Slovakia
13% Germany
15-18 % Europe, ( 0.3-232 per million of population)
On-line Hemodiafiltration: The Journey and the Vision. Sichart JM, Moeller S, 2011
A Survey among > 6000 nephrology professionals
showed that 80% consider dialysis with a high-flux
membrane superior to using a low-flux membrane, and
among them ∼ 50% prefer a convective therapy.
Ledebo I, Ronco C. The best dialysis therapy?. NDT Plus 2008
How supported by evidence?
DOPPS
2165 patients from 1998 to 2001 followed in
prospective observational study
DOPPS
35% lower mortality risk than
those receiving low-flux
After adjustments for all
variables, including dialysis dose (Kt/V)
DOPPS
- If all HD combined, low-efficiency HDF (RR 0.92, P. =0.066) and
for high-efficiency HDF again significantly lower
(RR. 0.64, P.=0.005).
- HDF pts. tended to have a greater likelihood of lower
inflammatory markers tested.
- Kt/V 1.44 (high efficiency) versus 1.35 (low-flux HD)
- Patients treated by HDF versus HD tended to be slightly older,
have higher body weight, and have longer average time on renal
replacement therapy (treating MD preference bias)
- It is possible that patients were preferentially selected for HDF
because of their higher weight and their poor clinical conditions,
specially cardiovascular diseases.
Nephrol Dial Transplant (2007) 22 [Suppl 2]
J Am Soc Nephrol 24: ccc–ccc, 2013
ESHOL
IS a multicenter, open-label, randomized controlled trial
assigned 906 chronic hemodialysis patients
to continue hemodialysis (n=450)
( approximately 92% were treated high-flux) or
to switch to high-efficiency OL-HDF (n=456).
(median replacement volume 20.8 to 21.8 L/session)
ESHOL
Primary and secondary outcomes:
• OL-HDF had a 30% lower risk of all-cause mortality (hazard ratio
[HR], 0.70; 95% confidence interval [95% CI], 0.53–0.92; P=0.01)
• OL-HDF had a 33% lower risk of cardiovascular mortality (HR, 0.67;
95% CI, 0.44–1.02; P=0.06)
• OL-HDF caused 61% risk reduction in mortality from stroke (HR,
0.39; 95% CI, 0.16– 0.93) (P=0.03)
• OL-HDF had a 55% lower risk of infection-related mortality (HR,
0.45; 95% CI, 0.21–0.96; P=0.03)
• OL-HDF 22% reduction of Hosp. (rate ratio, 0.78; 95% CI, 0.67–0.90;
P=0.001)
• OL-HDF 28% reduction in intradialysis hypotension(rate ratio,
0.72; 95% CI, 0.68–0.77; P,0.001)
NNT: 8 pts. To be switched to OL-HDF to prevent one annual death
ESHOL
Influence of Convection Volume on All-Cause Mortality:
post hoc analyses:
In the highest delivered convection volume, mortality
In intermediate tertile (23.1– 25.4 L) (HR, 0.60; 95% CI, 0.39–0.90)40%
In upper tertile (>25.4 L) (HR, 0.55; 95% CI, 0.34– 0.84) 45%
considered lower than that in patients randomized to HD.
Although all patient groups benefitted from OL-HDF, the subgroups
obtaining the greatest benefit were older, had no diabetes, were
dialyzed through an AVF, and had a higher Charlson comorbidity index
ESHOL
1-follow up, median 2.08 years(short)
2- 355/906 ( 40%) prematurely finished the study
• Pts. were withdrawn and not included in analyses if they did not
receive the allocated treatment modality for 2 months or more,
including those who did not achieve the minimum requested
replacement volume (18 L per session)(sicker pts.???)
3- No intention to treat analysis
4- RRF not monitored.
5- protocol violation
6- Higher mean Qb (387ml/min)than other studies.
7- β2-Microglobulin increased from month 0 to month 36 in both
groups but to a lesser extent in the OL-HDF group
J Am Soc Nephrol 23: 1087–1096, 2012
CONTRAST
Randomly assigned 714 chronic hemodialysis patients to
online postdilution hemodiafiltration (n=358)
or to continue low-flux hemodialysis (n=356)
• The primary outcome measure was all-cause mortality
• mean 3.0 years of follow-up (range, 0.4–6.6 years)
CONTRAST
Primary Outcome: All-Cause Mortality:
The incidence of all cause mortality was not affected by treatment
assignment (121 per 1000 person-years on hemodiafi ltration versus
127 per 1000 person-years on low-fl ux hemodialysis; hazard ratio
[HR], 0.95; 95% confidence interval [95% CI], 0.75– 1.20)
Secondary Outcomes:
NO difference between HDF and Low-Flux for CV events.
Clearance ond conective volume:
spKt/V urea increased in patients treated with hemodiafiltration (from
1.41 to 1.63, P< 0.001)
The average convection volume, which includes weight loss for HDF
pts. was 20.7 L/treatment session (median of 19.8 L), Target was: 24
L/treatment (6 L/h),
CONTRAST
Conductive volume:
HR for all-cause mortality was considerably lower in
the group of patients treated with the highest delivered
convection volumes (> 21.95 L; HR, 0.62; 95% CI, 0.38–
0.98)
CONTRAST
β-2 microglobulin levels
CONTRAST
1- Violation of the study protocol ( time on HDF and CV delivered
below target)
2- Inclusion of prevalent not incident patients
3- Selection bias
5- 33% of pts. Were censored before reaching the endpoint or
completing the study.
4- RRF not monitored
4-In December 2010, the board recommended to stop the trial
because enough evidence was provided for futility (i.e., no clear
efficacy of hemodiafiltration over hemodialysis)
TURKISH OL-HDF
A prospective, randomized, controlled trial of 782
chronic HD pts; (range 1.3–38.5 months)
• primary outcome: all-cause mortality and nonfatal
cardiovascular events
• Post-dilution OL-HDF ( 391 pts.), targeted
substitution volume 15 L / session
(96.7% >15 L, RV /session. Mean 17.2 ± 1.3 L )
• Conventional high-flux HD ( 391 pts.)
TURKISH OL-HDF
event-free survival rates after 36 months:
77.6% in OL-HDF and
74.8% in the HD group
P = 0.28
The overall & cardiovascular mortality: lower in OL-HDF ( Not
statically significant)
• independent predictors for primary outcome:
age (HR= 1.04, 95% CI 1.02– 1.06, P < 0.001)
diabetes (HR = 2.28, 95% CI 1.55– 3.37, P < 0.001)
AVF (HR = 0.41, 95% CI 0.20– 0.85, P = 0.01)
TURKISH OL-HDF
Mean IDWG was higher in OL-HDF (3.5 ± 1.9% in HDF versus 3.2
± 1.5% in HD, P = 0.01).
•
Predialysis plasma β -2 microglobulin levels no difference at
the end of the study (P = 0.94).
• erythropoietin dosage was significantly lower in the OL-HDF
P = 0.001)
No difference in hospitalization and intradialytic Hypotension
• OL-HDF Qb 318 ± 27 mL/min ( higher than HD,P < 0.001)
• eKt/V during follow-up was 1.44 ± 0.19 in the OL-HDF group,
significantly higher (P < 0.001)
TURKISH OL-HDF
• High-Flux HD
• Low-efficiency HDF (RF ≤ 17.4 L)
• High-efficiency HDF (RF > 17.4 L)
The relative risks of HE OL-HDF vs. high-flux HD
overall survival 0.54 (95% CI 0.33– 0.88, P = 0.01)
cardiovascular survival 0.31 (95% CI 0.14– 0.65, P =
0.002)
HE OL-HDF : 46% risk reduction for overall mortality [RR
= 0.54 (95% CI 0.31– 0.93) P = 0.02]
And 71% risk reduction for cardiovascular mortality [RR =
0.29 (95% CI 0.12– 0.65) P = 0.003]
Low-efficiency HDF (RF ≤ 17.4 L) vs. High-efficiency HDF (RF > 17.4 L)
post hoc analysis
TURKISH study
- 160 patients left the study for reasons other than
death
- 28% in HDF, 23% in HD did not finish the study
protocol
- Selection bias ( younger & healthier pts)
- The statistical power for this analysis was lower than
hypothesized
- Much lower than expected event rate
•
•
Sixty-five (29 crossover and 36 parallel-arm) (n = 12,182)
Statistically insignificant decrease in all-cause mortality
[relative risk (RR) 0.88; 95% confidence interval (CI) 0.76, 1.02,
P = 0.09]
• Cardiovascular mortality (RR 0.84; 95% CI 0.71, 0.98, P = 0.03)
• Decreased therapy-related hypotension (RR 0.55, 95% CI
0.35, 0.87, P = 0.01)
• Convective therapies had no impact on infection-related
mortality
Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc.
• In 2006, meta-analysis of 17 randomized trials (600
participants) comparing convective with diffusive
dialysis, convective modalities had uncertain effects
on mortality in low-quality evidence, and data for
adverse events were sparse.
published and unpublished data from randomized controlled trials
(RCTs) and quasi RCTs that evaluated convective dialysis therapies
(HDF, HF, or acetate-free biofiltration) compared with HD. Before
2006 plus after 2006 publications through Feb. 2013.
• Overall, 22 trials (3,217 participants) compared HDF
with HD, using fluid generated online (online HDF)
• Twelve trials (34%) used high-flux, 16 trials (46%)
used low-flux membranes, 4 trials (11%) used either
low- or high-flux membranes, and in 3 trials (9%),
membrane flux was unclear
• Convection strategies were highly heterogeneous
and no trial randomly assigned participants to
specific targeted convection volumes.
• 2,402 (59%) were derived from 3 large RCTs
evaluating online HDF
Risk of bias in all 35 trials
• Trials generally had very serious limitations due to
risks of bias in most domains leading to downgrading
of overall evidence quality.
• Risks of bias were high or unclear for sequence
generation (80% of RCTs) and allocation concealment
(all RCTs)
• Blinding of both participants and investigators was
not clearly reported in any trial
• There was selective reporting of outcomes in all
except 2 trials (94%).
• Of the 3 largest trials contributing to meta-analyses,
ESHOL; did not include 39.1% of randomly assigned
patients in analyses
Turkish Online HDF study, 20.5% of participants left the
study for reasons other than death, including 10% of
participants allocated to HDF due to vascular access
problems
• Adverse-event reporting was conducted at prespecified points during follow-up in 6 (17%) RCTs and
serious adverse events were not reported in any
study.
All cause mortality
CV mortality
All-Cause and Cardiovascular Mortality
• 11 trials (3,396 pts.) in low-quality evidence:
convective dialysis had little or no effect on allcause mortality (RR, 0.87; 95% CI, 0.70-1.07)
• In 6 RCTs ( 2,889 pts.), in low-quality evidence:
convective therapy may reduce death from
cardiovascular causes compared with HD (RR, 0.75;
95% CI, 0.58- 0.97)
All-Cause and Cardiovascular Mortality
Convective therapy might prevent 25 cardiovascular
deaths for every 1,000 patients treated for 1 year, but
has no significant effect on death overall.
• Very low-quality evidence: no difference in the
change in quality of life
• At a very significant heterogeneity
( I2 > 85% ) among the trials:
- Reduced predialysis serum β2-microglobulin levels
(in 12 RCTs mean difference, -5.77 [95% CI, -10.97 to 0.56] mg/dL)
- Increased Kt/V (14 RCTs; 2,115 participants)
mean difference, 0.10; 95% CI, 0.02- 0.19)
CONTRAST, ESHOL and TURKISH OL-HDF study;
Suggested better overall outcome with higher CV; this
conclusion might not be supported by acceptable
evidence level.
- NO randomization to high CV
- May had better accesses
- May received longer therapy time to achive high CV
• Data for adverse events were sparse, questions
about potential harms from convection therapy
cannot be answered with confidence using the
existing RCT evidence.
• Insufficient data was available to assess the effect of
RRF
In conclusion
• Convective dialysis modalities had little or no effect
on all-cause mortality and may reduce
cardiovascular death and hypotension during
dialysis, but had uncertain effects on rates of
nonfatal cardiovascular events and hospitalization.
• The available evidence quality is low or very low.
The true effects of treatment might be substantially
different.
Conclusion
1- OL-HDF is a safe modality of RRT provided high
standards of quality in water treatment are applied.
2- Effect in CV mortality POSSIBLY beneficial, but for
overall mortality, not yet.
3- The cost effectiveness is not well studied, but might
dissipate with time.
4- The available quality of evidence does not justify
making the OL-HDF therapy as the first line option or
the standard of care.
5- More high quality evidence is needed at this stage.