On-Line Hemodiafiltration
Authors: Martin K. Kuhlmann
Journal: Journal of the American Society of Nephrology (2012)

As the quest for better dialysis outcomes continues, the focus is shifting to a better removal of uremic toxins in the middle molecular weight range. Years ago, both the American Hemodialysis1 and the European Membrane Permeability Outcome2 studies failed to demonstrate a survival advantage for high-flux over low-flux hemodialysis (HD), although in both studies removal of the classic middle molecule β-2-micrglobulin (β2M) was significantly better with high-flux membranes. However, in both trials, specific subgroups were identified, for which high-flux treatment was associated with improved outcome, including patients with dialysis vintage >3.7 years, patients with diabetes, and patients with serum albumin levels <40 g/dl. It was argued that removal of middle molecular uremic toxins by high-flux HD may not have been effective enough to show a general survival differences and that more intense removal of those putatively atherogenic uremic toxins would certainly improve outcomes—just a question of time until that would be demonstrated. The basic understanding that better removal of uremic middle molecular weight substances may only be achieved by enhanced convective transport led to the development of new technologies for the on-line production of sterile, nonpyrogenic dialysate that can also be safely used as infusate. Among modern blood purification therapies, on-line hemodiafiltration (HDF) equipment allows much higher convection and substitution volumes than the earlier, fluid bag based HDF technology. On-line HDF therefore has the potential to provide the largest removal of the widest range of solutes. Documented advantages of on-line HDF include a higher removal rate for creatinine, phosphate, β2M, and some protein-bound uremic compounds.3 Several nonrandomized studies showed this may translate into potential clinical benefit, as demonstrated by sustained lower β2M and phosphate levels.4 On-line HDF is further associated with a lower incidence of intradialytic hypotension, improvements in erythropoietin responsiveness and nutritional status, prevention of inflammation, and better preservation of residual renal function.5,6 However, because of the lack of larger randomized studies, it remains a matter of debate whether these latter effects may have been related primarily to the treatment mode itself or secondary to improved dialysate purity. Despite these encouraging data, there was still a lack of convincing evidence of a survival benefit of HDF compared with standard conventional HD. This has now changed with the publication of the Convective Transport Study (CONTRAST) by Grooteman et al. in this issue of the JASN.7 The results of the CONTRAST trial are the first to be published out of a series of four randomized controlled studies comparing on-line HDF versus low- or high-flux HD, which were initiated some years ago in several European countries (The Netherlands, Turkey, France, and Spain). In CONTRAST, a total of 714 chronic HD patients were randomly assigned to either thrice-weekly 4-hour on-line HDF in postdilution mode or thrice-weekly 4-hour low-flux HD using on-line produced sterile dialysate. The results of the study, which was event driven with all-cause mortality as primary and the composite of fatal and nonfatal major adverse cardiac events as secondary end points, are somewhat puzzling: After a mean follow-up of almost 3 years, there was no difference in any of the predefined end points between the two treatment groups. Not even the predefined subgroup analysis according to age, sex, serum albumin, diabetes, residual renal function, type of vascular access, and dialysis vintage showed any differences in outcome. However, in secondary on-treatment analysis, a significantly better outcome was found for the subpopulation with a mean delivered convective volume exceeding 22 L/treatment, and this difference remained unaltered even after intense adjustment for potential confounders. Very similar findings have been reported from the randomized controlled Turkish Hemodiafiltration Study at the 2011 EDTA meeting in Prague, where no overall advantage for on-line HDF over high-flux HD was found in the total study population, whereas after on-treatment analysis, a significantly improved outcome was observed in the subgroup of patients treated with the highest convection volumes. The findings of the on-treatment analysis may be the clue for interpretation of the CONTRAST data. According to the study protocol, on-line HDF was strictly performed in the postdilution mode with a target convective volume of 24 L/treatment delivered within an average of 4 hours of treat-ment time. Because there was no evidence regarding the rela-tion between convection volume and outcome, these treatment targets were chosen arbitrarily based on maximal achievable convection volumes derived by modeling calculations. As treatment time was fixed, the major modifiable variables were dialyzer surface area, filtration fraction, and extracorporeal blood flow rate (Qb). To avoid an in-dialyzer hemoconcentration, a Qb between 300 and 400 ml/min was required to achieve the targeted convection volume of 6 L/h. However, in the vast majority of patients, these targets were clearly missed; the mean delivered convection volume was 20.7 L. In one-third of the study population, it was only 18 L or less. Thus, although not primarily intended by design, per-treatment and cumulative removal of larger solutes differed significantly among study participants. As pointed out by the authors, this appears to be a reflection of common practice, where it may be difficult to achieve the high Qb requirements because of inadequate vascular access. The major impact of CONTRAST may be the recognition that dosing matters, not only in HD, but also in HDF. Because of a lack of clinical data, dosing of HDF has not been a mat-ter of much debate; it still mainly relates to an arbitrarily prescribed absolute convection volume. Understanding that convective volume translates directly into uremic toxin mass removal, it is apparent that HDF dose needs to be better related to generation and distribution of those toxins. Uremic toxin generation, among other factors, depends on metabolic rate and visceral organ mass,8 whereas toxin distribution is affected by total body water, protein binding, and intracellular accumulation. In the future, HDF dose should therefore be normalized to a body size–related factor such as body weight or body surface area. In addition, complete and regular delivery of the individually prescribed target dose should become priority in HDF, with treatment time being an important variable in cases where inadequate vascular access limits blood flow rates. As demonstrated by the CONTRAST trial, higher convection volumes may be difficult to achieve in the postdilution mode. These limitations may be overcome with the mixed dilution HDF mode, where the replacement fluid is infused both upstream and downstream of the dialyzer, and the ratio of upstream and downstream infusion rates varies to achieve the optimal compromise between maximizing clearance and avoiding the consequences of hemoconcentration.9 The results of the CONTRAST trial should not be a cause for discouragement but rather be understood as a wake-up call for the development of unified international definitions of HDF itself and its adequacy. After a long time in which an advantage of on-line HDF over conventional HD was somehow taken for granted, it is now becoming clear that, to achieve the potential benefits of better middle molecule removal, HDF needs to be applied in an educated and well defined manner. Ongoing studies in this field will help to define future treatment standards. On-line HDF is not a self-fulfilling prophecy; it must be used wisely. Disclosures None.