Hemodiafiltration: principles and advantages over conventional HD. Rukshana Shroff Great Ormond Street Hospital for Children London, UK

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1 Hemodiafiltration: principles and advantages over conventional HD Rukshana Shroff Great Ormond Street Hospital for Children London, UK

2 Effectiveness of RRT modalities Mcfarlane, Seminars in dialysis, 2009

3 No benefit from increased urea clearance HEMO study, NEJM, 2002

4 HDF clearance by diffusion and convection

5 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

6 Advantages of HDF 1. Clearance of uraemic solutes across a wide molecular weight range 2. Biocompatibility 3. Hemodynamic stability

7 1. Clearance on HDF vs HD

8 β 2 microglobulin clearance HDF achieves 70 78% reduction in β 2 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, % 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 ß 2 M there is a 11% increase risk of death (HEMO Study) Cheung et al, JASN 2000

9 β2-microglobulin levels (mg/l) β 2 -microglobulin in our HD vs HDF patients p = 0.02 Significant association with convective volume (>15L/m 2 β 2 -microglobulin < 25mg/L) No further reduction Number of with children increasing time on HDF

10 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 recommended levels Number of children

FGF-23 levels (RU/mL) FGF-23 levels in our HD vs HDF patients p = 0.

11 FGF-23 levels (RU/mL) FGF-23 levels in our HD vs HDF patients p = % lower FGF-23 levels on HDF vs HD Significant association Number of children with convective volume

12 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)

13 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

14 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

15 Improved anaemia control on HDF Hemoglobin values and need for transfusions HD (12 months) HDF (12 months) Hb g/dl Number of transfusions for the whole group 32 (mean 5) 12 (mean 2) Membrane Cuprophane Polyacrylonitrile Duration (sessions) 3x5 h 3x3 h Fischbach et al; Ped Nephrol 1984

16 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

17 Cardiovascular and survival advantage of HDF vs HD

18 1. Dutch HDF Study: CONTRAST 1,2 1,0 Hazard Ratio 0,8 0,6 0,4 p= ,2 0,0 lowflux HD < 15.5 L L >20.3 L online HDF

19 2. Turkish HDF Study: High vs Low Efficiency HDF

20 3. Spanish HDF Study: High vs Low Efficiency HDF switching 8 patients from HD to HDF prevents one death / year

21 Regression of LVH on daily HDF 2D Graph 3 Posterior Wall thickness 2D Graph 2D Graph 3 3 Interventricular Septum Y Data 8 6 Y Data 8 6 Y Data O 2 2 6M 12M X Data O 6M 12M Fischbach X DataX Data et al; NDT 2004

22 Growth on HDF Fischbach et al, NDT 2010

23 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 % of children with ESRD grow up to become short adults (final height <3rd centile)

24 Growth study in children 15 children on daily HDF; mean age: 7.3 ( 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.

25 Growth on daily HDF NOTE: - High convective volume - Daily HDF Height SDS - start: -1.5 ± end: +0.2 ± 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

26 Dialysis efficiency & tolerance Mean weekly Kt/V urea =10 - dialysis dose ~ 35% GFR Phosphate: 1.39 ( ) 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

27 Diet and medications Start of daily HDF (n= 12) After 1 year on daily HDF (n=12) Diet Restricted Free (water, salt, proteins) Antihypertensive drugs 10/12 (>2 drugs/patient) 2/12 (1 drug/patient) Potassium chelators 12/12 4/12 (only on dialysis free day) Phosphate chelators Post dialysis recovery time 12/12 1/12 6 to 15 min No post-dialysis recovery time No sleep disturbances Improved appetite Improved physical activity Improved school attendance

28 Dialysis dose and growth Daugirdas et al; Clin JASN 2010

29 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

30 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

31 Nocturnal HD vs HDF x 3/wk Kt/V HD NHD NHDF NHD HD NHD NHDF NHD 150 Phosphate ipth 0

32 % prevalent patients on RRT <18 yrs from Paediatric HDF in Europe n=454 n=808 n=1281 n=2226 n=2494 Tx PD HD Percentage of patients cases of HDF in children in < 2 years 2-5 years 6-10 years years > 15 years (~12% of all HD cases) Age category ESPN/ERA-EDTA registry

Survey on current dialysis practice across Europe 47 responses 4 5 6 1 3 4 13 2 8 1 3 1 2 16 19 13

33 Survey on current dialysis practice across Europe 47 responses HD 210 children HDF 125 children ESPN/ERA-EDTA registry ~144 children on HDF across Europe

34 Choice of HD vs HDF

35 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) %

36 Potential limitations for setting up HDF 1. HDF machine 2. Water quality 3. Staff training 4. Costs 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 X provided by Fresenius / Gambro 40 /patient/month more than HD 5. No paediatric data We need a study!

37 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

38 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/m 2 (post-dilution) Dialysate purity equivalent in HD & HDF

39 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

40 Thank you! Participation in Clinical Trial Participation in IPHN Registry International Pediatric Hemodialysis Network

HEMODIAFILTRATION PRINCIPLES AND ADVANTAGES OVER CONVENTIONAL HD PRESENTATION BY DR.ALI TAYEBI

HEMODIAFILTRATION PRINCIPLES AND ADVANTAGES OVER CONVENTIONAL HD PRESENTATION BY DR.ALI TAYEBI high-flux Hemodiafiltration (HDF) Combination of two dialysis techniques, hemodialysis and hemofiltration: