Hemodiafiltration: Clinical Evidence of Higher Benefit Reference: Blankestijn PJ, LedeboI, Canaud B. Hemodiafiltration: Clinical evidence and remaining questions. Kidney International. 2010;77:581–587.

Worldwide, hemodialysis (HD) using high-flux membranes are currently well accepted (see Fig. 1). The rationale of its use is that it offers enhanced clearance of various uremic toxins by combining diffusion with some degree of convective transport within the dialyzer, which could be of relevance in determining clinical outcome.

However, two large randomized trials failed to show any survival benefits for the general HD population, when high flux dialysis was compared with dialysis with standard low flux membranes. Notably, the subgroups which did not benefit with the procedures were identified in both trials. This fact can be interpreted as showing that the intervention was useful only in certain high-risk patients but was not powerful enough to affect all patients. Moreover, harmful effects associated with high-flux membranes were not reported in any of the studies. As a result, the clinical data on hemodiafiltration (HDF), a technique that offers a greater advantage in clearance of various types of uremic toxins than HD with low- and high-flux membranes, was reviewed. The following review details about applying online HDF; as this technique has the potential to give the most pronounced enhanced clearance as compared to standard HD and other modes of HDF, and consequently conferring the greatest likelihood of benefit to the patient.

Technical Issues Associated with HD The ultrafiltration of fluid is required by the convective transport, to an extent that exceeds the desired weight loss. Moreover, fluid balance is maintained by infusion of a replacement fluid, also known as substitution fluid; which can be provided in industrially prepared, autoclaved, plastic bags. Logistically, this is troublesome and expensive, and hence is not widely accepted. Conversely, online HDF gives the option of quality-controlled, stepwise ultrafiltration. The substitution fluid is mixed with the blood and should therefore be sterile and non-pyrogenic with a composition similar to plasma water. Moreover, this high quality has to be continuously present.

Removal of Solute: Results with Online HDF Uremic toxins can be categorized into three groups: – Free water-soluble low-molecular-weight solutes, such as urea and creatinine – Middle-sized solutes, such as β 2 -microglobulin (β 2 m) – Protein-bound solutes, such as p-cresol An increase in small solute clearance is usually seen during the switch-over from either low- or high-flux HD to online HDF. This increase is modest as small solute clearance is mainly diffusive and therefore already very effective during HD. However, the removal of β 2 m is clearly increased during online HDF, and clearance of solutes in the middle molecule range might be of clinical relevance.

Removal of Solute: Results with Online HDF In the Hemodialysis (HEMO) Study, predialysis β 2 m levels predicted mortality, and several observational and randomized studies have shown that predialysis levels decrease when patients are switched to online HDF. A crossover study in which patients went from high-flux HD to online HDF and back, reported that online HDF markedly reduced production of TNF-α and IL-6 in addition to proinflammatory CD14+CD16+ cells. Improvement of variables related to endothelial dysfunction, oxidative stress, and antioxidant capacity was also attributed to the use of online HDF, besides this modality has shown to reduce advanced glycation end- products more effectively than high-flux dialysis. Thus, several lines of evidence testify that use of online HDF is associated with enhanced clearance small molecules, and several types of other molecules that might be of relevance in the pathogenesis of uremic and cardiovascular complications.

Clinical Variables Associated with Online HDF An improvement of clinically meaningful variables is associated with online HDF since it removes substances in a broader range of molecular size compared to conventional low-flux HD. Several studies suggested that online HDF was associated with an improvement of hemodynamic stability and blood pressure control; however certain other studies failed to confirm this. The difference in hemodynamic stability disappeared when online HDF was compared with temperature-controlled HD. Thus, this effect seemed to be mainly caused by cooling of the blood by enhanced thermal energy losses within the extracorporeal system in online HDF rather than from increasing solute removal. Studies also reported an improvement of nutritional parameters in patients when they were switched to online HDF.

Use of HDF: Effect on Survival Benefit Several retrospective analyses suggested that there could be a survival benefit in patients treated with HDF. Even after correction for various confounding factors, the use of high-efficiency HDF in the Dialysis Outcomes and Practice Patterns Study (DOPPS) cohort (replacement volume of more than 15 litres per session, which means online HDF in most cases for obvious logistical reasons) was associated with a 35% lower mortality risk. On the contrary, low efficiency HDF (replacement volume less than 15 litres per session) was not associated with any significant reduction of risk. A 37% mortality risk reduction was reported by another large observational study from Eastern Europe studying the effect of online HDF.

Use of HDF: Effect on Survival Benefit A single-center retrospective analysis from the United States reported that the standardized mortality ratio for patients treated with HDF (double high-flux HDF) was 0.41, indicating an almost 60% lower risk of mortality. Furthermore, a large Italian observational study suggested a survival benefit in patients on online HDF. Quite recently, a UK dialysis unit with long experience of HDF reported the outcome from some 150,000 sessions of online HDF compared with twice as many sessions of high-flux HD. They identified that the patients predominantly treated with HDF had a 34% lower mortality risk. Therefore, it can be hypothesized based on the evidence outlined above, that online HDF offers a superior treatment modality as compared to standard HD therapy.

Summary Penne et al. outlined the summary of factors that determined ultrafiltration. In addition to hematocrit, which is an important factor; modifiable treatment-related factors include treatment time and extracorporeal blood flow. Within the hematocrit range presently advised by Guidelines, the relation between ultrafiltration rate (i.e., convection) and extracorporeal blood flow rate can be 25– 35%. Table 1 lists the summary of the basic requirements which may guide the clinician to perform online HDF in everyday clinical practice. In conclusion, combining diffusive and convective strategies offers an interesting option. Currently, widely accepted is the standard use of high-flux membranes in HD, which can be considered as a ‘poor man’s HDF’. By applying online HDF, the combination of diffusive and convective transport can most efficiently be obtained, since it can provide larger convection volumes without major practical and economic constraints. The DOPPS findings provide the only data relating dose, which is convection volume per session, with clinical outcome. Currently available water treatment equipment and dialysis machines make it possible to perform online HDF on considerable scale in everyday clinical practice, besides suitable equipments are available with the main dialysis industries.

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