**4. Water for dialysis**

Possible pyrogenic reactions were considerable threat to patients on HDF since the risk of microbiological contamination with high substitution volumes was increased. Besides, costs were greater with increased substitution volumes used as well as with storage bags for them. Therefore, the need for the production of high purity substitution fluid at lower cost was a challenge, not only because of threatening pyrogenic reactions and financial constraints but also because of higher risk of accelerated atherosclerosis and malnutrition due to ongoing lowgrade inflammation [18]. Therefore, the American Association for the Advancement of Medical Instrumentation set the microbiological standards for water for dialysis at <200 colony-forming units (CFU) and <0.5 endotoxin units (EU)/ml. The European Pharmacopoeia was more stringent with <100 CFU and <0.25 EU/ml. Eventually, <0.1 CFU and <0.03 EU/ml were adopted for a solution to be considered "ultra-pure" and it is now widely used even for conventional haemodialysis [19].

"On-line" fluid production has enabled the concept of on-line HDF (oHDF). It facilitates the provision of an unlimited volume of sterile, non-pyrogenic substitution fluid not requiring storage, which is an efficient approach to prevent bacterial contamination and growth at a cost close to that of dialysate for conventional haemodialysis [20, 21]. The first step of the process includes the filtration of the water after it is produced using the reverse osmosis technique. The water is then used for the production of dialysate. This step has also been adopted in several haemodialysis machines to produce dialysate of improved purity. The second step includes further filtration of the dialysate. Finally, a third filtration by a disposable microfilter completes the creation of the substitution solution. The disposable microfilter is replaced at the end of the dialysis session. The dialysate prior to the last filtration is used for the diffusive element of HDF. The purity achieved using this approach has been repeatedly confirmed [21, 22] (**Figure 5**).

**Post-dilution HDF Pre-dilution HDF Mixed-dilution HDF**

fouling

and solute membrane permeability

Reduced solute clearance

substitution volume

and removal

Possible pyrogenic reactions were considerable threat to patients on HDF since the risk of microbiological contamination with high substitution volumes was increased. Besides, costs were greater with increased substitution volumes used as well as with storage bags for them. Therefore, the need for the production of high purity substitution fluid at lower cost was a challenge, not only because of threatening pyrogenic reactions and financial constraints but also because of higher risk of accelerated atherosclerosis and malnutrition due to ongoing lowgrade inflammation [18]. Therefore, the American Association for the Advancement of Medical Instrumentation set the microbiological standards for water for dialysis at <200 colony-forming units (CFU) and <0.5 endotoxin units (EU)/ml. The European Pharmacopoeia was more stringent with <100 CFU and <0.25 EU/ml. Eventually, <0.1 CFU and <0.03 EU/ml were adopted for a solution to be considered "ultra-pure" and it is now widely used even for conventional

"On-line" fluid production has enabled the concept of on-line HDF (oHDF). It facilitates the provision of an unlimited volume of sterile, non-pyrogenic substitution fluid not requiring storage, which is an efficient approach to prevent bacterial contamination and growth at a cost close to that of dialysate for conventional haemodialysis [20, 21]. The first step of the process

Requires specific hardware equipment and software

**Cons** Reduced fibres and membrane

Haemoconcentration Preserved hydraulic

Fibres and membrane fouling **Cons**

Reduced hydraulic and solute membrane

**Table 1.** Pros and cons of dilution modes.

**4. Water for dialysis**

haemodialysis [19].

permeability

Fibre clotting Potential alarms

Reduced sieving coefficient

10 Advances in Hemodiafiltration

Increasing membrane stress Potential albumin leakage HDF – Haemodiafiltration

Increased viscosity and oncotic pressure Reduced membrane stress

Increased transmembrane pressure Increased consumption of

**Figure 5.** One of the examples of water treatment system in the dialysis centre in Hemodialysis Unit of Lapeyronie Hospital in Montpellier (France) with microfilters depicted plus two microfilters within HDF machines (not depicted) showing the water for dialysis passing through HDF machines. The amount used ends up in the sewage; RO, reverse osmosis; HDF, haemodiafiltration.

So, an additional step to ensure full safety of dialysis and substitution fluids is to implement two sterilising ultrafilters built in within HDF machines on the path after the dialysate was prepared. They are disinfected regularly with the HDF machine and are replaced after a certain time of use as defined by manufacturer.

From an economic perspective, the added cost of the ultrafilters used to prepare the substitu‐ tion solution has been nullified because of growing tendency of using ultra-pure dialysate even in conventional haemodialysis, thereby leaving the only difference in cost in the amount of water consumed per treatment. Above all, the remaining cost has been balanced by the biochemical and clinical benefits of HDF [20].
