Hemodiafiltration:
principles and advantages
over conventional HD
Rukshana Shroff
Great Ormond Street Hospital for Children
London, UK
Effectiveness of RRT modalities
Mcfarlane, Seminars in dialysis, 2009
No benefit from increased urea
clearance
HEMO study, NEJM, 2002
HDF – clearance by diffusion and
convection
Outline

Mechanisms of hemodiafiltration (HDF)
- theoretical advantages

Clinical benefits of HDF vs conventional HD
- lessons from adult studies
- focus on growth and nutrition
- in-centre nocturnal HDF

Survey across EU

Research study – effects of HDF vs HD on
growth & cardiovascular outcomes in children
Advantages of HDF
1. Clearance of uraemic solutes across a wide
molecular weight range
2. Biocompatibility
3. Hemodynamic stability
1. Clearance on HDF vs HD
β2microglobulin clearance

HDF achieves 70 – 78% reduction in β2 microglobulin
(vs 40 – 50% with high-flux HD) Thomas et al, Semin Dialy, 2009

No signs of amyloidosis after 8 yrs on HDF (vs 100%
pts on HD have amyloid by 13 yrs) Canaud et al, NDT, 1998

82% reduced incidence of carpal tunnel syndrome
and 67% reduced incidence of erosive arthritis
Dember et al, Semin Dialy, 2006

For every 10 mg /l increase in predialysis ß2M there is
a 11% increase risk of death (HEMO Study)
Cheung et al, JASN 2000
β2-microglobulin
levels (mg/L)
β2-microglobulin in our HD vs HDF patients
p = 0.02
• Significant association with convective volume
(>15L/m2 β2-microglobulin < 25mg/L)
Number ofwith
children
• No further reduction
increasing time on HDF
Pre-dialysis phosphate levels (mg/L)
Phosphate levels in our HD vs HDF
patients
• No difference between HDF vs HD (p = 0.07)
• 9/15 on HD vs 13/15 on HDF achieved KDOQI
Number of children
recommended levels
FGF-23 levels in our HD vs HDF patients
FGF-23 levels (RU/mL)
p = 0.003
• 29% lower FGF-23 levels on HDF vs HD
Number of children
• Significant association
with convective volume
Other middle molecules cleared
by HDF
 Parathyroid hormone
 Inflammatory cytokines (IL-6, IL-8, IL-12)
 Homocysteine
 Guanidine
 Polyamines
Influence endothelial function:
- Reduce nitric oxide production
- Promote AGE formation
- Affect cell cycle and cause senescence
 Appetite suppressants (leptin, cholecystokinin,
tryptophan)
2. Reduced inflammation and
oxidative stress
1.
2.
3.
4.
reduces inflammation ( TNF, IL-6, IL-8, IL-12)
suppresses oxidative stress ( reactive oxygen
species and superoxide)
improves antioxidant capacity
reduces generation of AGEs
Mechanisms
1. Biocompatible membranes
2. ‘Ultrapure’ dialysate
3. Removal of cytokines
Chronic low-grade exposure to endotoxins

Chronic inflammation

Anorexia, poor nutrition and growth, catabolism,
loss of lean body mass – cachexia

Anaemia – poor ESA response

Risk of atherosclerosis
Malnutrition – inflammation – atherosclerosis complex
Improved anaemia control on HDF
Hemoglobin values and need for transfusions
HD (12 months)
HDF (12 months)
7.4
8.3
Number of
transfusions for the
whole group
32 (mean 5)
12 (mean 2)
Membrane
Cuprophane
Polyacrylonitrile
3x5 h
3x3 h
Hb g/dl
Duration (sessions)
Fischbach et al; Ped Nephrol 1984
3. Hemodynamic stability
1.
2.
3.
4.
Fewer intra-dialytic hypotensive episodes
Higher UF better tolerated by patient
Reduced post-dialysis fatigue
Overall better BP control
Mechanisms:
1. Cooling of dialysate
2. Removal of vasodilating mediators
3. High Na content of infusion fluid
Cardiovascular and
survival advantage of HDF
vs HD
1. Dutch HDF Study: CONTRAST
1,2
Hazard Ratio
1,0
0,8
p=0.016
0,6
0,4
0,2
0,0
lowflux HD
< 15.5 L
15.5-20.3 L
online HDF
>20.3 L
2. Turkish HDF Study:
High vs Low Efficiency HDF
3. Spanish HDF Study:
High vs Low Efficiency HDF
switching 8 patients from HD to HDF
prevents one death / year
Regression of LVH on daily HDF
2D Graph
33
2D Graph
Interventricular Septum
14
14
12
12
12
10
10
10
8
8
8
6
Y Data
14
Y Data
Y Data
2D Graph 3
Posterior Wall thickness
6
6
4
4
4
2
2
2
O
0
0
0
6M
12M
0
1
1
X Data
O
6M
12M
0
0
2
2
1
1
X Data
X Data
Fischbach
et al; NDT 2004
Growth on HDF
Fischbach et al, NDT 2010
Nutrition & growth in children
on dialysis
Growth failure is a common end point of
multiple CKD-related abnormalities :

•
•
Malnutrition – anorexia and reduced energy
intake
Cachexia - protein energy wasting - due to
chronic inflammation and inadequate dialysis
35 - 50 % of children with ESRD grow up
to become short adults (final height <3rd
centile)

Growth study in children

15 children on daily HDF; mean age: 7.3 (2.8 –
16.7 yrs)

7 converted from PD & 5 from 3/week HD

Vascular access: fistula (n=13) & catheter (n=4)

Pre-dilution HDF; Qb & Qd adjusted to achieve a
Kt/Vurea ≥1.4 per session x 18 hours per week
Fischbach et al; NDT, 2010
Growth on daily HDF
NOTE:
- High convective volume
- Daily HDF
Height SDS
start: -1.5 ± 0.3
- end: +0.2 ± 1.1
- target height relative to midparental height: +0.3
-
Height velocity
- before daily HDF: 3.8 ±1.1
cm/y
- first year of daily HDF:
14.3 ± 3.8 cm/
- mean : 10.4
cm/y
Fischbach
et al; NDT, 2010
Dialysis efficiency & tolerance

Mean weekly Kt/Vurea =10
- dialysis dose ~ 35% GFR

Phosphate: 1.39 (1.65 - 0.63) mmol/l
- despite high protein intake (>2 g/kg/day)
- 2/15 child on chelators


CRP – normal in 13/15 (2 children had chronic
infections)
β2 microglobulin 13.5 ± 3.5 mg/L
Diet and medications
Start of daily HDF
(n= 12)
Diet
Antihypertensive
drugs
Potassium
chelators
After 1 year on daily HDF
(n=12)
Restricted
Free
(water, salt, proteins)
10/12
(>2 drugs/patient)
2/12
(1 drug/patient)
12/12
4/12
(only on dialysis free day)
Phosphate
chelators
Post dialysis
recovery time
12/12
6 to 15 min
1/12
No post-dialysis recovery time
No sleep disturbances
Improved appetite
Improved physical activity
Improved school attendance
Dialysis dose and growth
Daugirdas et al; Clin JASN 2010
Anabolic effect of daily HDF

Stimulates appetite - removal of circulating satiety
factors (leptin, cholecystokinin, tryptophan)

Correction of metabolic acidosis. Acidosis can:
- activate the ubiquitin-proteosome pathway & increase
protein degradation
- suppresses endogenous GH secretion

Minimises inflammatory cytokine release

? Removal of somatomedin and gonadotropin
inhibitors by HDF

? reverses rhGH resistance
Schaefer et al, NDT 2010
HDF in an in-centre nocturnal
dialysis programme

n = 7 children

Convective volume per session was > 30 liters
Thumfart T, Muller D et al; Ped Nephrol 2014
Nocturnal HD vs HDF x 3/wk
120
100
80
60
Kt/V
40
20
HD
NHD
NHDF
0
NHD 450
HD
NHD
NHDF
NHD
400
350
300
250
200
150
Phosphate
100
50
0
iPTH
Paediatric HDF in Europe
n=454
n=808
n=1281
n=2226
n=2494
% prevalent patients on RRT <18 yrs
from 2007Percentage
- 2012 of patients
100
Tx
PD
HD
80
60
40
20
144 cases of HDF in children in 2012
(~12% of all HD cases)
0
< 2 years
2-5 years
6-10 years
11-15 years
> 15 years
Age category
ESPN/ERA-EDTA registry
Survey on current dialysis practice across Europe
47 responses
4
5
6
1
3
4
2
8
3
13
16
1
1
2
19
19
13
11
2
HD – 210 children
HDF – 125 children
ESPN/ERA-EDTA registry ~144 children on HDF across Europe
Choice of HD vs HDF
Reasons for not doing HDF
Total – 19 responses
43%
Lack of
machines
Lack of
‘ultrapure’
water
Cost
Staff not
trained
HDF is
not
better /
safe
Vascular
access
does not
permit HDF
Multiple
reasons
Type of access (% patients per centre)
Central line median 62 (IQR 0 – 84) %
Fistula
median 30 (IQR 0 – 60) %
Potential limitations for setting
up HDF
1.
HDF machine
X newer machines can all do HDF
- one time installation cost, then 1-3 monthly
monitoring
- must use ultrapure water with all high flux
membranes
2.
Water quality
3.
Staff training
X provided by Fresenius / Gambro
4.
Costs
€40 /patient/month more than HD
5.
No paediatric data
 We need a study!
The effects of HDF vs conventional HD
on growth and cardiovascular markers in
children
n
3H (HDF, Hearts and Height) study
International Pediatric
Hemodialysis Network
Hypothesis
Children on HDF compared with HD have improved:
 Cardiovascular risk profile
 Growth and nutritional status
 Quality of life
Rukshana.Shroff@gosh.nhs.uk
Primary outcome measures:


Change in carotid artery intima-media thickness SDS over 1year
Change in height SDS over 1-year
Secondary outcome measures:

Nutritional status, cardiovascular status and quality of life
Inclusion criteria:


All children 4 - 20 years age (incident and prevalent patients)
Kt/v>1.2 in prevalent HDF and HD patients
Exclusion criteria:

if living donor kidney transplant is planned within 6-months
Study design


1:1 study design
Recruitment for 2 years, follow-up minimum 12-months
Numbers needed 150 children (75 in each study arm)
Standard prescriptions for HDF and HD


Aim for target convection volume of 12-15L/m2 (post-dilution)
Dialysate purity equivalent in HD & HDF
Summary

HDF offers many advantages over HD
- improved clearance of uraemic toxins
- biocompatibility
- hemodynamic stability

HDF is not widely practiced in children

Ongoing study to examine effects of HDF on
growth and cardiovascular outcomes
Thank you!
Participation in Clinical Trial
Rukshana.Shroff@gosh.nhs.uk
Participation in IPHN Registry
Claus.Peter.Schmitt@med.uni-heidelberg.de
International Pediatric
Hemodialysis Network