Hemodialysis vs. Hemodiafiltration

1. Hemodialysis vs. Hemodiafiltration Hemodialysis Symposium 8-9 February, 2014 Al-Madinah Al-Munawwarah, KSA SaadAlobaili KKUH, KSU Riyadh

3. Main Uremic Toxins

5. 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

6. 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) • Iisdetermined 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.

7. 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.

8. I. Ledebo and P. J. Blankestijn, NDT plus 2010

9. Determinantsof Convective Transport Across Membranes: • 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)

10. 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)

11. Dialyzers are classified as: - Some refer to “FLUX” as ability to remove ß2-M. - High-Flux dialyzers: are considered convective dialyzers ( Filtration and back filtration of6-8 L over 4hs conventional HD session.

13. LedeboI. Principles and practice of hemofiltration and hemodiafiltration.ArtifOrgans 1998; 22: 20–25

14. Both the Hemodialysis (HEMO) study and the Membrane Permeability Outcome (MPO) study compared low-flux hemodialysis with high-flux hemodialysis. Neither study showed a difference in mortality risk between the treatment arms. In HEMO, High-flux HD was associated with an 8% non-significant 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.

15. Uremic solutes with known negative impact on the cell systems involved in atherogenesisand the clinical development of cardiovascular and cerebrovascular problems, CV mortality rate is still 10 times higher than in thegeneral populationJAmSocNephrol 9[Suppl]: S16–S23, 1998 Vanholder et alTheInternational Journal of Artificial Organs / Vol. 24 / no. 10, 2001

16. Normal β2 microglobulin level: 1-2 mg/L Targeted in HD population 15-20 mg/L

18. RISCAVID Prospective study of 757 HD patients, followed for 30 months • HD (n = 424) • Haemodiafiltration with sterile bags (n = 204) • online HDF (n = 129)

19. 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)

20. 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)

21. HDF is a blood purification therapy combing diffusive and convective solutetransport 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.

22. 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)

23. 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

24. 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

25. 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.

26. Substitution Fluid Preparation steps:

28. 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

29. Achieving higher convection volumes • Higher Qb • Higher serum albumin • Lower hematocrit high haemoglobinand low albumin may attenuate convection by reducing filtration fraction

30. Substitution solutionenters extrakorporal circuitafterdialyzer Best removal of small and middle size uremic toxins – filtration from undiluted blood! But … ultrafiltration limited by haemoconcentration high blood viscosity secondary protein layer membrane polarization and high blood flow rates are needed Substituate(post) HDF pump blood pump Postdilution On-Line HDF blood (out) Filtrate (UF + HDF) blood (in) The filtration rate should be limited to 40% of plasma water flow rate, corresponding to 25% of blood flow rate. EBPGD 2007

31. Substitution solution enters extracorporeal circuit before dialyser Improved membrane permeability- filtration from diluted blood! But … dilution also reduces efficiency lower diffusion gradient reduced clearance for small molecules blood (out) Filtrate (UF + HDF) HDF pump Substituate (pre) blood pump blood (in) Predilution On-Line HDF

33. 2010-2011 • 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

34. 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. LedeboI, Ronco C. The best dialysis therapy?. NDT Plus 2008

35. How supported by evidence?

36. DOPPS 2165 patients from 1998 to 2001 followed in prospective observational study

37. DOPPS 35% lower mortality risk than those receiving low-flux After adjustments for all variables, including dialysis dose (Kt/V)

38. 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.

39. Nephrol Dial Transplant (2007) 22 [Suppl 2]

40. J Am Soc Nephrol 24: ccc–ccc, 2013

41. 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)

42. 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

43. 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 Charlsoncomorbidity index

44. 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

45. J Am Soc Nephrol 23: 1087–1096, 2012

46. CONTRAST Randomly assigned 714 chronic hemodialysis patients to online postdilutionhemodiafiltration (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)

47. CONTRAST Primary Outcome: All-Cause Mortality: The incidence of all cause mortality was not affected by treatment assignment (121 per 1000 person-years on hemodiafiltration versus 127 per 1000 person-years on low-flux 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 ondconective 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),

48. 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)

49. CONTRAST

50. β-2 microglobulin levels