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 in our HD vs HDF patients

p = 0.02
β2-microglobulin
levels (mg/L)

• Significant association with convective volume

(>15L/m2 β2-microglobulin < 25mg/L)
• No further reduction
Number ofwith increasing time on HDF
children
 Phosphate levels in our HD vs HDF
patients
Pre-dialysis phosphate levels (mg/L)

• No difference between HDF vs HD (p = 0.07)

• 9/15 on HD vs 13/15 on HDF achieved KDOQI

recommended levels
Number of children
 FGF-23 levels in our HD vs HDF patients

p = 0.003
FGF-23 levels (RU/mL)

• 29% lower FGF-23 levels on HDF vs HD

• Significant association with convective volume

Number of children
 Other middle molecules cleared
by HDF

 Parathyroid hormone
 Inflammatory cytokines (IL-6, IL-8, IL-12)
 Homocysteine
Influence endothelial function:
 Guanidine - Reduce nitric oxide production
- Promote AGE formation
 Polyamines - Affect cell cycle and cause senescence

 Appetite suppressants (leptin, cholecystokinin,

tryptophan)
 2. Reduced inflammation and
oxidative stress

1. reduces inflammation ( TNF, IL-6, IL-8, IL-12)

2. suppresses oxidative stress ( reactive oxygen
species and superoxide)
3. improves antioxidant capacity
4. 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)

Hb g/dl 7.4 8.3

Number of 32 (mean 5) 12 (mean 2)

transfusions for the
whole group
Membrane Cuprophane Polyacrylonitrile

Duration (sessions) 3x5 h 3x3 h

Fischbach et al; Ped Nephrol 1984

 3. Hemodynamic stability

1. Fewer intra-dialytic hypotensive episodes

2. Higher UF better tolerated by patient
3. Reduced post-dialysis fatigue
4. 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

1,0

0,8
Hazard Ratio

p=0.016

0,6

0,4

0,2

0,0
lowflux HD < 15.5 L 15.5-20.3 L >20.3 L
online HDF
 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 3 2D Graph 33
2D Graph
Posterior Wall thickness Interventricular Septum
14 14 14

12 12 12

10 10 10

8 8

Y Data
8
Y Data
Y Data

6 6 6

4 4 4

2 2 2

O 6M 12M O 6M 12M
0 0
0
0
1 0 2 1 1
0 1 2

X Data Fischbach
X Data et al; NDT 2004
X Data
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 Height velocity

- start: -1.5 ± 0.3 - before daily HDF: 3.8 ±1.1
- end: +0.2 ± 1.1 cm/y
- target height relative to mid- - first year of daily HDF:
parental height: +0.3 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 After 1 year on daily HDF
(n= 12) (n=12)
Diet Restricted Free
(water, salt, proteins)
Antihypertensive 10/12 2/12
drugs (>2 drugs/patient) (1 drug/patient)
Potassium 4/12
chelators 12/12
(only on dialysis free day)
Phosphate
12/12 1/12
chelators
Post dialysis No post-dialysis recovery time
6 to 15 min
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

0
HD NHD NHDF NHD 450
HD NHD NHDF NHD

400

350

300

250

200

150
Phosphate
100
iPTH
50

0
 Paediatric HDF in Europe

n=454 n=808 n=1281 n=2226 n=2494

100
Tx
% prevalent patients on RRT <18 yrs

PD
HD
80
- 2012 of patients

60
from 2007Percentage

40

20

144 cases of HDF in children in 2012 0

< 2 years 2-5 years 6-10 years 11-15 years > 15 years

(~12% of all HD cases) Age category

ESPN/ERA-EDTA registry
Survey on current dialysis practice across Europe

47 responses
4 1
3 2
5 4
1 1
8
6 2
13 3

16 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 Lack of Cost Staff not HDF is Vascular Multiple

machines ‘ultrapure’ trained not access reasons
water better / does not
safe permit HDF
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

2. Water quality monitoring
- must use ultrapure water with all high flux
membranes

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 1-
year
 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