**2. Uremic toxins and hemodialysis techniques**

The new medium cut-off membrane/dialyzer, with its larger pore size, lower wall thickness, and smaller inner diameter of hollow fibers, has significantly improved the clearance of the large-size uremic toxins in safe, simple, and effective technique, especially when compared to conventional hemodialysis techniques [9]. For example, the low-flux HD can remove small soluble solutes less than 500 Dalton (Da), such as urea and creatinine, whereas high-flux HD is capable of efficiently removing molecules less than 15,000 Da. Diffusion is the major contributor to the clearance of smallsize molecules, but convection, as in online hemodiafiltration (HDF), is required for the efficient removal of large-size molecules, especially those above 25,000 Da [7]. Randomized controlled trials have shown the effectiveness of online HDF not only in its ability to remove large-size uremic toxins but to improve the quality of life [10] and to significantly reduce the cardiovascular and all-cause mortality, especially if the used prescribed convection volume equals to or exceeds 23 liters/1.73 m2 /session [11]. However, successful implementation of online HDF is demanding. For example, it requires a special HD machine that has the ability to mix solutions online, a powerful high-flux dialyzer, functional vascular access with a blood flow rate of 350–400 ml/

minute (difficult with central venous catheters or not properly functioning arteriovenous fistula or graft), consumption of large volume of water (almost double what is needed for conventional HD), ultrapure water (free from bacteria and endotoxin), frequent monitoring of water quality, training of medical and nursing staff (especially when the turnover is frequent) and achievement of the prescribed convective volume [12].

The actual value of the medium cut-off membrane/dialyzer is its ability to perform diffusion and convection with fluid replacement (internal filtration) internally simulating, and probably more effective than, online HDF, without the need for external replacement fluids [13], using a basic HD machine with a blood flow rate of 250–300 ml/minute [14], and standard water quality (ISO11663 or ANSI/AAMI RD62) [15–21] for conventional HD over the 4-hours dialysis session. This modality of HD is referred to as HDx or expanded hemodialysis [9]. HDx therapy has been shown to remove effectively larger-size uremic toxins [22], improvement of quality of life [23–26], reduction in HD-related medications (e.g., erythropoietin and iron) [27, 28], and a significant decrease in hospitalization rate [29, 30] and nonfatal cardiovascular disease [18].
