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

Molecular weight range Classification Molecular weight range Small molecules e.g. urea (60), creatinine (113), phosphate (134) < 500 Middle molecules e.g. vitamin B12 (1355), vancomycin (1448), inulin *5200, endotoxin fragments (1000-15,000) parathormone (9425), ß2-m (11,818) 500 – 15,000 Large molecules e.g. myoglobulin (17,000), RBP (21,000), α 1-m (26,700), EPO (30,000), albumin (66,000), transferrin (90,000) > 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: 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) β2-Microglobulin Clearance ( mL/min) Conventional ≤ 12 ≤ 10 High-flux > 14 ( > 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% 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.

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)

Diffusion + convection (UF) for excess fluid removal 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 Dialysate Ultrapure dialysate <0.1 <0.03 Substitution fluid for infusion Sterile <10−6 Undetectable

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! But … ultrafiltration limited by haemoconcentration high blood viscosity secondary protein layer membrane polarization and high blood flow rates are needed blood (out) Substituate (post) HDF pump Filtrate (UF + HDF) blood pump blood (in) Substitution solution enters extrakorporal circuit after dialyzer 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 Filtrate (UF + HDF) blood (in) blood pump Substituate (pre) HDF pump blood (out) Improved membrane permeability - filtration from diluted blood! But … dilution also reduces efficiency lower diffusion gradient reduced clearance for small molecules Substitution solution enters extracorporeal circuit before dialyser

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

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 23-25 = 40% Mortality risk reduction > 25L= 45% M. risk reduction

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 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. -(-):--- 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 pre- specified 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 all-cause 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.