Is hemodiafiltration ready for broader use?
Authors: Thomas A. Golper
Journal: Kidney International (2015)

Hemodiafiltration is practiced throughout Europe and in a few additional countries but, because of regulatory restrictions, is not currently available in the United States. Hemodiafiltration removes uremic species more broadly than is achieved by diffusion dialysis, perhaps explaining its better outcome profile. Hemodiafiltration is practiced throughout Europe and in a few additional countries but, because of regulatory restrictions, is not currently available in the United States. Hemodiafiltration removes uremic species more broadly than is achieved by diffusion dialysis, perhaps explaining its better outcome profile. Survival of hemodialysis patients in Europe has consistently been superior to that observed in the United States. Initially, by the European perspective, this was attributed to superior care and dialytic techniques. But as data acquisition and analysis became more sophisticated, it became clear that at least part of the difference in mortality was attributable to a more liberal ‘take-on’ rate in the United States; that is, sicker patients presented to end stage, and a larger fraction of those presenting at end stage in the United States were dialyzed. That explanation allowed Americans to feel better and perhaps complacent. The initial suspicion that care and technique differences might explain the outcome divergence was not particularly studied. However, those of us familiar with these differences were uncomfortable. Our European colleagues paid more attention to treatment time, ultrafiltration rate and total ultrafiltration volume, dialysate water quality, membrane flux, patient-physician exposure time, and better hemodialysis vascular access preparation. At least for the type of dialysis available in the United States, the HEMO and Membrane Permeability Outcome (MPO) studies suggested a benefit of higher flux and thus the removal of uremic toxins beyond the size of small solutes. In this issue of Kidney International an argument is made that a large convective addition to diffusive dialysis may impart a major survival advantage. Canaud and others have been advancing the science of hemodiafiltration (HDF) for at least three decades. He and his Dialysis Outcomes and Practice Patterns Study (DOPPS) colleagues suggested a survival benefit in patients receiving HDF compared with even high-flux hemodialysis in Europe.1.Canaud B. Bragg-Gresham J.L. Marshall M.R. et al.Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS.Kidney Int. 2006; 69: 2087-2093Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar European dialysis equipment manufacturers have developed novel systems to generate large volumes of sterile substitution fluids cheaply and efficiently. These systems do not exist in the United States, to some extent owing to regulatory barriers imposed by the US Food and Drug Administration (FDA). As the value of HDF becomes more evident, the divergence in European and US dialysis outcomes will continue. Canaud et al.2.Canaud B. Barbieri C. Marcelli D. et al.Optimal convection volume for improving patient outcomes in an international incident dialysis cohort treated with online hemodiafiltration.Kidney Int. 2015; 88: 1108-1116Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar (this issue) now attempt to answer what is the convection volume dose above which a survival benefit is derived. They followed 2634 incident patients receiving HDF in eight Eurasian countries. Within that cohort they propensity-score-matched 204 pairs, comparing convection volumes of those less than 54.6 liters per week and greater than 64.8 liters per week. Those in the higher convection volume dose group demonstrated a threefold higher survival. Of the original 2634 patients, 2293 were included in cubic spline analyses. From that group the survival rate increased at a convection volume dose around 55 liters per week (30 liters/week/m2) and plateaued at 70–75 liters per week (40–45 liters/week/m2). So we have an approximation from about 1600 patients as to what convection volume dose starts to associate with improved survival and an approximate dose above which no survival enhancement is noted. Obviously sample sizes affect our confidence, but the trends are clear. These results showing effects of convection volume dose on outcome are consistent with randomized controlled trials such as ESHOL (Spain),3.Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.J Am Soc Nephrol. 2013; 24: 487-497Crossref PubMed Scopus (490) Google Scholar the Turkish Online HDF Study,4.Ok E. Asci G. Toz H. et al.Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF study.Nephrol Dial Transplant. 2013; 28: 192-202Crossref PubMed Scopus (333) Google Scholar and CONTRAST,5.Grooteman M.P.C. van den Dorpel M. Bots M.L. et al.Effect of online hemodiafiltration on allcause mortality and cardiovascular outcomes.J Am Soc Nephrol. 2012; 23: 1087-1096Crossref PubMed Scopus (381) Google Scholar as well as with large observational studies such as that from the United Kingdom6.Vilar E. Fry A.C. Wellsted D. et al.Long-term outcomes in online hemodiafiltration and high-flux hemodialysis: a comparative analysis.J Am Soc Nephrol. 2009; 4: 1944-1953Crossref Scopus (133) Google Scholar and the DOPPS mentioned earlier.1.Canaud B. Bragg-Gresham J.L. Marshall M.R. et al.Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS.Kidney Int. 2006; 69: 2087-2093Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar One criticism of the present study by Canaud et al. 2.Canaud B. Barbieri C. Marcelli D. et al.Optimal convection volume for improving patient outcomes in an international incident dialysis cohort treated with online hemodiafiltration.Kidney Int. 2015; 88: 1108-1116Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar is that we do not know how the convection volume doses were determined for each patient. The weekly convection volume was pretty consistent for each patient over the 2-year course. But readers and the authors do not know how that dose was determined. There was no prespecified dosing guideline, and the dose varied from 30 to 95 liters per week with the majority between 60 and 75 liters per week. The authors were asked to address this omission during the review process. Most of the convection volume dose determination is almost automatic in that, for example, a target might be set at 100 ml/min, and in a postdilution mode that may represent 25% of the blood flow rate. We do not know whether the convective volume dose was specified by the center—that is, a center-specific prescribed dose. Patients with accesses that can tolerate a very high blood flow rate are most likely to have larger convection volume doses if the session duration is fixed. This is likely to have occurred in the Turkish trial.4.Ok E. Asci G. Toz H. et al.Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF study.Nephrol Dial Transplant. 2013; 28: 192-202Crossref PubMed Scopus (333) Google Scholar While the type of access can be adjusted for, and was in many of the studies mentioned above, I do not think the ability of the access to allow a higher blood flow rate and thus convection volume dose was specifically adjusted for. I argue that this is a form of confounding by indication, given that the best accesses allow for the greatest convection volume dose, and these ideal accesses are by themselves the predictors of better survival. Of course, longer treatment time compensates for lower blood flow rate. Although I doubt this is the case, in a similar line of reasoning one cannot rule out another confounding by indication where sicker patients are prescribed a lower convection volume dose or in some way other than vascular access cannot tolerate a higher convection volume dose. Thus, the lower mortality is selection of healthier patients to a higher convection volume dose, and outcome is not convection volume dose dependent. I prefer to think that confounding by indication is not occurring and that convection volume doses in the range of 30–70 liters/week/m2 are associated with better outcomes. Why? It is not likely to be due to small-solute clearance as clearly shown in almost all of these studies. Urea clearance as a surrogate for other small solutes is not different across the spectrum of convection volume doses studied. Convective therapies are more effective than diffusive therapies in removing larger molecules (Figure 1). The authors speculate that lower β2-microglobulin and C-reactive protein (CRP) levels are either possible explanations or at least markers for other molecules that might be better removed by large convection volume doses. In addition to its role in dialysis-associated amyloidosis, β2-microglobulin is associated with peripheral vascular disease and arterial stiffness in patients with end-stage renal disease,7.Wilson A.M. Kimura E. Harada R.K. et al.β2-Microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies.Circulation. 2007; 116: 1396-1403Crossref PubMed Scopus (149) Google Scholar so its reduction may be directly beneficial. The argument for CRP is less clear because of its size and the lower likelihood that it is removed convectively. However, high convective flux can increase surface area as membrane pores are exposed and could thus increase adsorption. But a molecule the size of CRP is not likely to enter membrane pores and adsorb there. So this relationship to improved outcomes and reduction in CRP levels is still elusive. Some other inflammatory species are beneficially affected by higher convection volume doses. Perhaps other smaller inflammatory species may be adsorbing because of exposure of pore surface area to high convective flux. In addition, in a series of studies to explore why HDF may lead to better outcomes than even high-flux hemodialysis, Meert and her colleagues have shown in a small number of patients that some protein-bound solutes perceived to be uremic toxins are more effectively removed by HDF compared with high-flux hemodialysis,8.Meert N. Waterloos M.-A. Van Landschoot M. et al.Prospective evaluation of the change of predialysis protein-bound uremic solute concentration with postdilution online hemodiafiltration.Artif Organs. 2010; 34: 580-585Crossref PubMed Scopus (59) Google Scholar, 9.Meert N. Eloot S. Waterloos M.-A. et al.Effective removal of protein-bound uraemic solutes by different convective strategies: a prospective trial.Nephrol Dial Transplant. 2009; 24: 562-570Crossref PubMed Scopus (140) Google Scholar but valid skepticism about this mechanism remains. So at least theoretically, there are several lines of evidence to support that convective solute transport is advantageous over diffusion-dominated dialysis and it is probably convection volume dose dependent. The equipment needed to perform HDF is currently available, and broader application, including in the United States, may prove to be beneficial. Hopefully this will help to improve dialysis quality, thereby reducing dialysis complications and mortality. The author declared no competing interests.