**5. Summary**

whom target convection volumes are not achieved by post-dilution HDF because of high

Mid-dilution HDF similarly combines pre- and post-dilution fluid reinfusion into a hybrid system (**Figure 7**). It does so by utilising a specialised haemodiafilter, the Nephros OLpur MD 190. This filter is constructed in such a way that blood enters through the central core fibres of the dialyser and returns in the opposite direction peripherally. This model effec‐ tively comprises two dialysers in series. Substitution fluid is incorporated at the midpoint of the system, which creates an initial post-dilution stage followed by a pre-dilution stage. This enables a high-concentration gradient and encourages movement of small solutes in the first stage and maximal ultrafiltration of plasma water and convective removal of larger mole‐

Unfortunately, due to the nature of the specialised dialyser, mid-dilution HDF is associated with higher costs. There is also a higher degree of albumin loss, which is not insignificant. Concerns exist regarding generation of a high TMP, which could compromise membrane permeability. A TMP of up to 1000 mmHg has been reported as necessary to achieve the required minimum ultrafiltration of 6 L/h [30]. This high TMP is especially problematic in the first section of the dialyser where the post-dilution phase takes place and is thought to be the result of partial fibre clotting and increased resistance to blood flow due to the reduced capillary diameter in this segment [31]. Given the pro-coagulant effect of rapid convection, adequate anticoagulation is necessary to ensure device patency. Reversal of the configuration of the blood tubing (i.e. connecting the arterial line to the venous port of the dialyser and vice versa) has been successfully trialled in mid-dilution HDF without significant effect on plasma clearances if adequate infusion rates are maintained [32, 33]. Consideration should also be

When compared to post-dilution HDF, mid-dilution HDF is associated with inferior small solute but superior middle-molecule clearance (β2M, myoglobin, prolactin, RTP) and similar clearance of protein-bound solutes [35–37]. With increasing molecular weight, differences in treatment efficiency between mid- and post-dilution HDF rise [36]. Phosphate clearance is similar between the two groups. Whilst few studies have compared mid- and mixed-dilution HDF, one small prospective randomised trial found greater small-solute and middle-molecule clearance with mixed-dilution HDF though differences in dialyser membranes may have confounded their outcomes [30]. Another small prospective crossover study compared 'simple mid-dilution' (using two dialysers in series, rather than the Nephros OLpur MD 190) and mixed-dilution HDF. They similarly found that mixed-dilution HDF provided significantly greater clearances of urea, creatinine and β2M compared To 'simple mid-dilution' HDF with equivalent phosphate clearances [38]. These outcomes require examination in larger trials.

Two novel systems, '*pre-dilution on demand*' and '*backflush on demand*', have recently been proposed as potential alternatives to the standard online HDF modalities [39]. These sys‐

haematocrit, high plasma protein, or inadequate vascular access and blood flow rate.

cules in the second stage. Reinfusion rates up to 10–12 L/h are possible.

given to the use of larger-surface filters (e.g. Nephros OLpur MD 220) [34].

**4.4. Mid-dilution HDF**

38 Advances in Hemodiafiltration

**4.5. Novel systems**

Many questions remain unanswered in the field of fluid convection, generation and reinfu‐ sion in haemodiafiltration. Although convection volume appears to have a dose-dependent relationship with survival, randomised trials have failed to consistently demonstrate im‐ proved mortality in their primary analyses. Furthermore, the critical 'dose' required to im‐ prove patient outcomes is yet to be determined and may need to be individualised according to patient factors, including patient size and residual renal function. Online gener‐ ation of ultrapure dialysate has revolutionised the practice of HDF by allowing large con‐ vection volumes, although this approach requires strict monitoring in terms of quality and safety. The preferred site of fluid reinfusion is not known and warrants careful considera‐ tion of the opposing factors of solute clearance efficiency and the consequences of haemo‐ concentration. Hybrid modalities appear to present a promising balance between the two. Given the lack of robust clinical trials confirming the benefits of HDF, the increasing uptake of HDF worldwide has largely been driven by industry. Lack of a harm signal, cost neutral‐ ity and optimism that patient benefits will arise from large convective volumes have facili‐ tated acceptance amongst the Nephrology community. It is unclear whether high-quality data from randomised trials will be available to guide convection and reinfusion strategies and it is likely that practice will need to rely on the results of observational studies.

### **Author details**

Emily J. See1 , Carmel M. Hawley1 , John WM. Agar2 and David W. Johnson1\*

\*Address all correspondence to: david.johnson2@health.qld.gov.au

1 University of Queensland at Princess Alexandra Hospital, Brisbane, Australia

2 University Hospital Geelong, Geelong, Australia
