**6. Towards more cardioprotective renal replacement therapy**

Enhanced clearances of middle molecules such as beta-2 microglobulin [28] and phosphate [29] and other small molecules, such as homocysteine and complement D factor [30] are the

On-line monitoring of blood parameters allows adjustment of ultrafiltration rate to identify the patient-specific exchange rate possible at any given point in time while enabling haemo‐ dynamic stability. The substitution rate is adjusted to blood flow rate, thereby controlling haemoconcentration, whereas blood flow rate is adjusted to dialysis flow rate to control diffusion [31] (as for the diffusion component on-line clearance monitoring is used and the goal is to achieve spKt/V of 1.4). Therefore, if the blood flow rate drops from 100 L to 70 L per session, and the total UF volume remains at 25 L, the filtration fraction rises from 25% to 37% (**Figure 9**), which may generate a lot of difficulty during the session, lot of alarms and lot of critical TMP notifications, and the session may not end with a volume that was targeted.

main biochemical benefits of convective-based treatment over conventional HD.

*5.1.3. Blood flow as a limiting factor for high-volume haemodiafiltration*

14 Advances in Hemodiafiltration

**Figure 9.** The impact of blood flow on filtration fraction.

In the very beginning of oHDF era, both the physician and the nurse in charge were supposed to do manual interventions in an attempt to prescribe and to keep the desired convective volume for each individual patient, respectively. The physician was able to do manual calculation based on the formula that included optimal blood flow rate, desired ultrafiltration rate to compensate for interdialytic weight gain, haematocrit, total proteins and filter per‐ formance, which was frequently producing alarms indicating threatening haemoconcentration and possible membrane fouling due to an excessive ultrafiltration rate. Therefore, the nurse had to carefully monitor the TMP (indicator of threatening problems) and react during the session in three possible ways in order to prevent TMP from reaching critical level: (a) rinse the dialyser with substitution fluid or normal saline, (b) decrease the UF rate or (c) switch to conventional haemodialysis. The latter two interventions were reducing the anticipated convective volume in the dialysis prescription, whereas the former intervention was only temporarily fixing the problem.

The advanced technology of automatic adaptation by the built-in software AutoSub®, Fresenius Medical Care or Ultracontrol®, Baxter, was later developed in order to achieve alarm-free setting and to avoid the related problems, so that no manual calculation was needed any more by the physician in charge, but yet not all parameters with impact on flow conditions and blood viscosity were considered in formula. Therefore a nurse still had to do manual interventions because warning notification used to be received by the built-in software in order to opt for (a) ignoring the warning; (b) accepting the warning and letting the software reduce the UF at a new recommended rate in order to be within a safe range and prevent TMP from reaching critical level, albeit reducing the expected convective volume defined at the beginning of the session; or (c) turning off software monitoring. Besides, the nurse can always turn off the substitution pump and switch to HD.

Finally, with the development of the new technology for automatic ultrafiltration control in the dialyser, alarm-free maximisation of substitution volumes has been achieved, which is based not only on information about conditions across the membrane but also along the blood flow pathway in the dialyser, so that calculation of substitution volume based on the param‐ eters specified above has become obsolete [32]. This was shown in a crossover study of patients treated during 240-min sessions on the same day with three different blood flow rates (QB300, QB350 and QB380) and switched after two consecutive weeks from conventional HDF to this new technology. The convective volumes were 24.8 ± 3.1, 27.8 ± 3.0, 28.8 ± 2.4 and 23.9 ± 1.2, 27.2 ± 1.9, 28.5 ± 2.1, respectively (*p* > 0.05), to provide the evidence that the biological markers specified above are not needed for each and every haemodialysis session in order to achieve optimisation of the procedure [33].

This innovative technology is known as AutoSub plus mode [32] (**Figure 10**).

**Figure 10.** Switch from manual to automatic mode. TMP, transmembrane pressure.

**Figure 10** shows the red line in manual mode favouring increasing convective volume and efficacy, whereas yellow line represents safety and favours TMP limitations, which means that TMP increases over time during the dialysis session as convective volume increases. However, in automatic mode on the right side of **Figure 10**, the optimisation of substitution volume has been achieved by setting the safety target range so that the machine itself sets the safe TMP target range and continuously regulates the optimal UF rate at an optimal time throughout the session in order to keep the TMP in optimal range to prevent haemoconcentration and membrane complications specified above (**Table 1**). However, the nurse can still switch to manual mode or even to conventional HD should extraordinary conditions prevent highvolume oHDF (such as special rheologic properties of a patient's blood) [32]. Owing to continuous analysis of haemorheological conditions throughout the dialysis session, contin‐ uous adaptation of UF flow takes place (**Figure 11**).

**Figure 11.** Continuous adaptation of ultrafiltration flow in AutoSub plus mode while keeping UF loss constant; red line within the dialyser illustrates dynamic analysis of pressure pulses along the blood flow pathway; UF, ultrafiltrate to be lost during the dialysis session; HDF, haemodiafiltration; FF, filtration fraction; QUF, ultrafiltrate flow; QB, blood flow.

For this improvement sieving coefficient for beta-2 microglobulin was further increased to 0.9 in a new series of Cordiax© dialysers (**Figure 12**).

**Figure 12.** New series of Cordiax© dialysers with sieving coefficient for beta-2 microglobulin of 0.9 achieved by wid‐ ened pore diameter which permits better molecule removal, but still retention of albumin (simplified graph based on manufacturer's internal data).

The result is the improved removal of middle molecules (while ensuring the retention of albumin) due to increased filtration fraction, thereby generating increased substitution fluid volumes, with no need to even keep the high blood flow rate, so that equally adequate dialysis can also be delivered to patients with suboptimal blood flow rates (such as inpatients with poor vascular access or inadequate needle size). This technology introduced the concept of high-volume oHDF with substitution volumes >20 L as well as the related concept of cardio‐ protective haemodialysis due to its beneficial effects of cardiovascular system. It introduced the new era of high-volume cardioprotective renal replacement therapy as the major clinical effect of high-volume oHDF.
