**2. Historic background**

In an attempt to reduce mortality, it was postulated in 1983 that a higher Kt/V than commonly prescribed during conventional short dialysis may increase survival among patients under‐ going renal replacement therapies [5]. However, the hemodialysis (HEMO) study failed to show a positive effect on patient survival when dialysis dose per haemodialysis session was increased above the current K/DOQI recommendations [6]. Possible explanation for this unfavourable outcome could be in the kinetics of urea removal which is representative of small solutes, but not of larger sized molecules such as middle molecules, large-molecular-weight proteins or protein-bound solutes, thereby making Kt/V misleading. Clearance of urea accounts for only one-sixth of physiological clearance [1]. In addition, several shortcomings are associated with short dialysis schedules that are not captured by Kt/V index such as extracellular fluid volume control, phosphate control and adequate removal of middle and larger uremic molecules compounds.

Beta-2 microglobulin levels are associated with the development of dialysis-related amyloi‐ dosis and possibly reduced survival [7]. It seems likely that beta-2 microglobulin is a marker for overall middle-molecule clearance, including more toxic and as yet unidentified uremic compounds [8–11]. Those solutes are better removed by high-flux membranes compared to low-flux membranes due to their more porous characteristics with increased permeability.

Whether survival differs upon exposure to randomly assigned high- or low-flux membranes was also evaluated in the HEMO study [6]. No difference was observed. The same result was obtained in the Membrane Permeability Outcome study, in which patients were also randomly assigned to high- or low-flux dialysis membranes [12].

by the European Uremic Toxin Work Group. Sixty-eight have a molecular weight less than 500Da, 10have amolecularweightbetween500 and12,000Da and12 exceed12,000Da.Twentyfive solutes (28%) are protein bound [1]. These figures are further increasing with the adop‐

The clearance of solutes during conventional haemodialysis (HD) depends on their size and the concentration gradient across the dialysis membrane. Solutes weighing less than 500 Da are considered low-molecular-weight solutes and they are removed by passive diffusion down a favourable concentration gradient. Urea is considered a marker of such toxins. Its clearance, as measured by Kt/Vurea, correlates with patient morbidity [2] showing the evidence that such

However, despite improvements in technology and patient care, the mortality rate of patients on maintenance dialysis remains high, at approximately 15–20% per year [3]. As specified in the United States Renal Data System report, the expected remaining life span after the initiation of renal replacement therapy was eight years for dialysis patients aged 40–44 and 4.5 years for those 60–64 years of age. In general population the ranges of the expected remaining life span at specified ages are 30–40 years and 17–22 years, respectively. The values in older dialysis patients are only slightly better than those in patients with lung cancer [4]. Therefore, there is an obvious need to change the practices and to attempt to approach the problem differently.

In an attempt to reduce mortality, it was postulated in 1983 that a higher Kt/V than commonly prescribed during conventional short dialysis may increase survival among patients under‐ going renal replacement therapies [5]. However, the hemodialysis (HEMO) study failed to show a positive effect on patient survival when dialysis dose per haemodialysis session was increased above the current K/DOQI recommendations [6]. Possible explanation for this unfavourable outcome could be in the kinetics of urea removal which is representative of small solutes, but not of larger sized molecules such as middle molecules, large-molecular-weight proteins or protein-bound solutes, thereby making Kt/V misleading. Clearance of urea accounts for only one-sixth of physiological clearance [1]. In addition, several shortcomings are associated with short dialysis schedules that are not captured by Kt/V index such as extracellular fluid volume control, phosphate control and adequate removal of middle and

Beta-2 microglobulin levels are associated with the development of dialysis-related amyloi‐ dosis and possibly reduced survival [7]. It seems likely that beta-2 microglobulin is a marker for overall middle-molecule clearance, including more toxic and as yet unidentified uremic compounds [8–11]. Those solutes are better removed by high-flux membranes compared to low-flux membranes due to their more porous characteristics with increased permeability.

Whether survival differs upon exposure to randomly assigned high- or low-flux membranes was also evaluated in the HEMO study [6]. No difference was observed. The same result was

tion of new knowledge and technology of uremic toxins detection.

toxins contribute to the uremic syndrome.

6 Advances in Hemodiafiltration

**2. Historic background**

larger uremic molecules compounds.

In an attempt to improve patients' outcomes, alternative renal replacement therapies have been developed, since removal by diffusion becomes less efficient as the molecular weight of a solute increases. Therefore, the need to mimic the kidney function seems to become manda‐ tory in order to enhance middle-molecule removal because the diffusion in the tubules and loop of Henle follows filtration in glomerulus, which is the principle of convection (**Figure 1**).

**Figure 1.** Mimicking native kidney function to enhance middle-molecule removal.

Haemofiltration (HF) is the treatment modality that employs convection in order to facilitate removal of larger molecular weight solutes while using high-flux dialysers only. In convection the small- and large-molecular-weight solutes are removed in the ultrafiltrate by solvent drag. Although HF is effective in the removal of the larger molecular weight solutes, it is less effective in the removal of small molecules as it is restricted by the magnitude of the ultrafiltration volume achievable. Haemodiafiltration (HDF) is the treatment modality that combines diffusion and enhanced convection in order to facilitate removal of small-molecular-weight solutes. Moreover, small-molecule removal is further increased with the use of high-volume on-line HDF (HV oHDF) (see section "Towards more cardioprotective renal replacement therapy") and can be higher than haemodialysis, depending upon the volume of the replacement solution [13].

The ratio between treatment techniques, processes and molecular weights of the solutes is shown in **Figure 2**.

**Figure 2.** The ratio between treatment techniques, processes and molecular weights of solutes. HD, haemodialysis; HDF, haemodiafiltration; HF, haemofiltration; KoA, mass transfer area coefficient; QB, blood flow; tHD, duration of HD session; SC, sieving coefficient (the proportion of a substance to be removed for a particular filter).

The utilization of convective therapies has been variable. Between 1998 and 2001, about 12% of patients were on HDF in the European countries participating in the Dialysis Outcome and Practice Patterns Study (DOPPS) study [14].

There have not been too many studies to compare the patients' survival between convective modalities and high-flux HD. One of them was Italian MAMHEBI study, which was a randomised controlled trial (RCT). Significantly higher three-year survival was noted with HF (68% versus 52%) [15]. Dialysis Outcome and Practice Patterns Study (DOPPS) was prospective observational study which showed better survival with HDF, but it compared high-efficiency HDF with composite predictor of high- and low-flux haemodialysis [14]. Vilar et al. conducted retrospective cohort study and showed better survival with on-line HDF than with high-flux haemodialysis [16], as well as Imamović et al. in incident patients' population [17], but the latter three were epidemiological studies and RCT to show survival benefit of HDF over conventional HD was still missing.
