Biochemical and Clinical Benefits of HDF

HDF provides an enhanced clearance of β2-microglobulin and osteocalcin compared to HD (30–40% higher with HDF than with high-flux HD) (1). Several large cohort studies indicate that extended use of convective therapies has a beneficial impact on the development of β2-microglobulin amyloidosis (2,3), reducing the incidence of carpal tunnel syndrome and other related mani­festations. This beneficial effect probably results from the regular use of ultrapure fluids and less bioincompatible materials that could help to prevent inflammation, combined with convective transport mechanisms that enhance β2-microglobulin removal (4-13). 

A prospective study, based on direct dialysis quantification methodology, found that phosphate removal was enhanced by 15–20% with post-dilution HDF compared to high-flux HD (14).

Studies indicate higher clearances of a number of other solutes with HDF, including complement factor D (a pro-inflammatory mediator) (15), leptin (16kDa, involved in loss of appetite) (16), FGF23 (30kDa, implicated in metabolic bone disorders and vascular calcification) (17,18), PTH (19), various cytokines (13,20,21), and circulating advanced glycation end products (AGEs) and AGE precursors (22). 

Several prospective studies, including RISCAVID, have shown that levels of CRP (C-reactive protein) and other sensitive biomarkers of inflammation (e.g., IL-6) and/or proinflammatory cells are reduced with HDF (23). A recent meta-analysis suggested that a low inflammatory profile, associated with long-term use of HDF, relies most probably on regular exposure to ultrapure dialysis fluid and is less likely due to removal of pro-inflammatory mediators (24).

Erythropoiesis-stimulating agent (ESA) dose could be reduced in several clinical studies with HDF, the benefit being attributed to the combined effects of the higher removal of middle-sized retention solutes (erythropoietic inhibitor substances), the use of higher quality water, and reduced inflammation (25). However, the extent to which HDF might reduce ESA resistance compared to HD remains uncertain, with no effect found in a preplanned secondary analysis of a prospective randomized trial (26) or in a recent meta-analysis (27). Nevertheless, a significant decrease was observed in patients treated with erythropoetin in a large observational study (28).

A significant reduction in the number of intradialytic hypotension episodes was observed with HDF compared to conventional HD; this was also seen in high cardiovascular risk patients (29). Hemodynamic stability benefit of HDF is usually ascribed to the negative thermal balance (i.e., hypothermic dialysis) due to infusion of relatively cool substitution fluid, rather than a high sodium concentration in the substitution fluid and/or removal of vasodilation mediators (30, 31, 32).

Nutritional status preservation is a crucial parameter for dialysis adequacy. Despite potential increased losses of amino acids and/or nutrients due to its higher efficiency, HDF tends to better preserve body composition and nutritional status compared to HD, even in malnourished patients (33, 34). In a prospective one-year follow-up study, HDF-treated patients had better preservation of muscle mass, increased protein intake and reduced inflammatory state compared to high-flux HD, supporting the hypothesis that appropriate HDF dosing favors physical activity, benefits nutritional status, and prevents protein-energy wasting in HD patients (35).

Optimal bone mineral disease management, an important component to prevent progression of bone disease and vascular calcification, may be facilitated by HDF (36). HDF was shown to have beneficial effects on mineral and bone biomarkers in a cross-sectional study (19). In the CONTRAST study, pre-dialysis serum phosphate levels were reduced by 6% at steady state, and the percentage of patients reaching target pre-treatment serum phosphorus levels increased from 64% to 74% (37). Potential pathways for this could involve increased removal rate of FGF23 (+20%), improved response to calcidiol (+30%), but there are conflicting results on the levels of sclerostin and of alkaline phosphatase (18, 38-41). However, it is important to note that divalent ion prescription (calcium, magnesium), treatment time and phosphate binder type (calcium- or non-calcium-based) are still major confounders in interpretation of bone mineral biomarker changes (42-44).

Health-Related Quality of Life (HRQOL) studies have provided conflicting results (45). Several crossover studies support a beneficial role of HDF in enhancing quality of life. However, most parallel-group randomized clinical trials on this subject demonstrate no or limited improvement in HRQOL associated with HDF. The available data on HRQOL in patients under HDF is limited and of low quality. The inconsistency of these results is probably related to different methods used to assess quality of life, heterogeneity of population studies, and variations in convective dose delivered.


  1. Maduell F, Navarro V, Cruz MC, Torregrosa E, Garcia D, Simon V, et al. Osteocalcin and myoglobin removal in on-line hemodiafiltration versus low- and high-flux hemodialysis. Am J Kidney Dis. 2002;40(3):582-9.
  2. Locatelli F, Marcelli D, Conte F, Limido A, Malberti F, Spotti D. Comparison of mortality in ESRD patients on convective and diffusive extracorporeal treatments. The Registro Lombardo Dialisi E Trapianto. Kidney Int. 1999;55(1):286-93.
  3. Nakai S, Iseki K, Tabei K, Kubo K, Masakane I, Fushimi K, et al. Outcomes of hemodiafiltration based on Japanese dialysis patient registry. Am J Kidney Dis. 2001;38(4 Suppl 1):S212-6.
  4. Di Iorio B, Di Micco L, Bruzzese D, Nardone L, Russo L, Formisano P, et al. Ultrapure dialysis water obtained with additional ultrafilter may reduce inflammation in patients on hemodialysis. J Nephrol. 2017;30(6):795-801.
  5. Upadhyay A, Susantitaphong P, Jaber BL. Ultrapure versus standard dialysate: A cost-benefit analysis. Semin Dial. 2017;30(5):398-402.
  6. Arizono K, Nomura K, Motoyama T, Matsushita Y, Matsuoka K, Miyazu R, et al. Use of ultrapure dialysate in reduction of chronic inflammation during hemodialysis. Blood Purif. 2004;22 Suppl 2:26-9.
  7. Krieter DH, Lemke HD, Canaud B, Wanner C. Beta(2)-microglobulin removal by extracorporeal renal replacement therapies. Biochim Biophys Acta. 2005;1753(1):146-53.
  8. Lin CL, Yang CW, Chiang CC, Chang CT, Huang CC. Long-term on-line hemodiafiltration reduces predialysis beta-2-microglobulin levels in chronic hemodialysis patients. Blood Purif. 2001;19(3):301-7.
  9. Lornoy W, Becaus I, Billiouw JM, Sierens L, van Malderen P. Remarkable removal of beta-2-microglobulin by on-line hemodiafiltration. Am J Nephrol. 1998;18(2):105-8.
  10. Tattersall J. Clearance of beta-2-microglobulin and middle molecules in haemodiafiltration. Contrib Nephrol. 2007;158:201-9.
  11. Ward RA, Greene T, Hartmann B, Samtleben W. Resistance to intercompartmental mass transfer limits beta2-microglobulin removal by post-dilution hemodiafiltration. Kidney Int. 2006;69(8):1431-7.
  12. Mandolfo S, Borlandelli S, Imbasciati E. Leptin and beta2-microglobulin kinetics with three different dialysis modalities. Int J Artif Organs. 2006;29(10):949-55.
  13. Panichi V, De Pietro S, Andreini B, Migliori M, Tessore V, Taccola D, et al. Cytokine production in haemodiafiltration: a multicentre study. Nephrol Dial Transplant. 1998;13(7):1737-44.
  14. Lornoy W, De Meester J, Becaus I, Billiouw JM, Van Malderen PA, Van Pottelberge M. Impact of convective flow on phosphorus removal in maintenance hemodialysis patients. J Ren Nutr. 2006;16(1):47-53.
  15. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W. A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol. 2000;11(12):2344-50.
  16. Kim S, Oh KH, Chin HJ, Na KY, Kim YS, Chae DW, et al. Effective removal of leptin via hemodiafiltration with on-line endogenous reinfusion therapy. Clin Nephrol. 2009;72(6):442-8.
  17. Miao LY, Zhu B, He XZ, Liu JF, Jin LN, Li XR, et al. Effects of three blood purification methods on serum fibroblast growth factor-23 clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis. Exp Ther Med. 2014;7(4):947-52.
  18. Patrier L, Dupuy AM, Granger Vallée A, Chalabi L, Morena M, Canaud B, et al. FGF-23 removal is improved by on-line high-efficiency hemodiafiltration compared to conventional high flux hemodialysis. J Nephrol. 2013;26(2):342-9.
  19. Małyszko J, Małyszko JS, Koźminski P, Pawlak K, Wołczynski S, Myśliwiec M. Markers of bone metabolism in hemodialyses and hemodiafiltration. Ren Fail. 2007;29(5):595-601.
  20. Kuo HL, Chou CY, Liu YL, Yang YF, Huang CC, Lin HH. Reduction of pro-inflammatory cytokines through hemodiafiltration. Ren Fail. 2008;30(8):796-800.
  21. Ağbaş A, Canpolat N, Çalışkan S, Yılmaz A, Ekmekçi H, Mayes M, et al. Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children. PLoS One. 2018;13(6):e0198320.
  22. Lin CL, Huang CC, Yu CC, Yang HY, Chuang FR, Yang CW. Reduction of advanced glycation end product levels by on-line hemodiafiltration in long-term hemodialysis patients. Am J Kidney Dis. 2003;42(3):524-31.
  23. Panichi V, Rizza GM, Paoletti S, Bigazzi R, Aloisi M, Barsotti G, et al. Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. Results from the RISCAVID study. Nephrol Dial Transplant. 2008;23(7):2337-43.
  24. Susantitaphong P, Riella C, Jaber BL. Effect of ultrapure dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters: a meta-analysis. Nephrol Dial Transplant. 2013;28(2):438-46.
  25. Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S, et al. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26(8):2641-8.
  26. van der Weerd NC, Den Hoedt CH, Blankestijn PJ, Bots ML, van den Dorpel MA, Lévesque R, et al. Resistance to erythropoiesis stimulating agents in patients treated with online hemodiafiltration and ultrapure low-flux hemodialysis: results from a randomized controlled trial (CONTRAST). PLoS One. 2014;9(4):e94434.
  27. Susantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2013;28(11):2859-74.
  28. Marcelli D, Bayh I, Merello JI, Ponce P, Heaton A, Kircelli F, et al. Dynamics of the erythropoiesis stimulating agent resistance index in incident hemodiafiltration and high-flux hemodialysis patients. Kidney Int. 2016;90(1):192-202.
  29. Mion M, Kerr PG, Argiles A, Canaud B, Flavier JL, Mion CM. Haemodiafiltration in high-cardiovascular-risk patients. Nephrol Dial Transplant. 1992;7(5):453-4.
  30. Maggiore Q, Pizzarelli F, Dattolo P, Maggiore U, Cerrai T. Cardiovascular stability during haemodialysis, haemofiltration and haemodiafiltration. Nephrol Dial Transplant. 2000;15 Suppl 1:68-73.
  31. van der Sande FM, Kooman JP, Konings CJ, Leunissen KM. Thermal effects and blood pressure response during postdilution hemodiafiltration and hemodialysis: the effect of amount of replacement fluid and dialysate temperature. J Am Soc Nephrol. 2001;12(9):1916-20.
  32. Maggiore Q, Pizzarelli F, Santoro A, Panzetta G, Bonforte G, Hannedouche T, et al. The effects of control of thermal balance on vascular stability in hemodialysis patients: results of the European randomized clinical trial. Am J Kidney Dis. 2002;40(2):280-90.
  33. Savica V, Ciolino F, Monardo P, Mallamace A, Savica R, Santoro D, et al. Nutritional status in hemodialysis patients: options for on-line convective treatment. J Ren Nutr. 2006;16(3):237-40.
  34. Murtas S, Aquilani R, Deiana ML, Iadarola P, Secci R, Cadeddu M, et al. Differences in Amino Acid Loss Between High-Efficiency Hemodialysis and Postdilution and Predilution Hemodiafiltration Using High Convection Volume Exchange-A New Metabolic Scenario? A Pilot Study. J Ren Nutr. 2019;29(2):126-35.
  35. Molina P, Vizcaíno B, Molina MD, Beltrán S, González-Moya M, Mora A, et al. The effect of high-volume online haemodiafiltration on nutritional status and body composition: the ProtEin Stores prEservaTion (PESET) study. Nephrol Dial Transplant. 2018;33(7):1223-35.
  36. Elsayed HM, Elsharkawy MM, Kamel CR, Hussein HS, Abdelgawad MA, Abdelsamea MS. Effect of hemodiafiltration on sclerostin level and bone specific alkaline phosphatase in comparison with high flux dialysis. QJM: An International Journal of Medicine. 2020;113(Supplement_1).
  37. Penne EL, van der Weerd NC, van den Dorpel MA, Grooteman MP, Lévesque R, Nubé MJ, et al. Short-term effects of online hemodiafiltration on phosphate control: a result from the randomized controlled Convective Transport Study (CONTRAST). Am J Kidney Dis. 2010;55(1):77-87.
  38. Cornelis T, van der Sande FM, Eloot S, Cardinaels E, Bekers O, Damoiseaux J, et al. Acute hemodynamic response and uremic toxin removal in conventional and extended hemodialysis and hemodiafiltration: a randomized crossover study. Am J Kidney Dis. 2014;64(2):247-56.
  39. Jia T, Qureshi AR, Brandenburg V, Ketteler M, Barany P, Heimburger O, et al. Determinants of fibroblast growth factor-23 and parathyroid hormone variability in dialysis patients. Am J Nephrol. 2013;37(5):462-71.
  40. Potier J, Bowry S, Canaud B. Clinical Performance Assessment of CorDiax Filters in Hemodialysis and Hemodiafiltration. Contrib Nephrol. 2017;189:237-45.
  41. Pérez-García R, Albalate M, de Sequera P, Alcázar R, Puerta M, Ortega M, et al. On-line haemodiafiltration improves response to calcifediol treatment. Nefrologia. 2012;32(4):459-66.
  42. Argilés A, Kerr PG, Canaud B, Flavier JL, Mion C. Calcium kinetics and the long-term effects of lowering dialysate calcium concentration. Kidney Int. 1993;43(3):630-40.
  43. Spoendlin J, Paik JM, Tsacogianis T, Kim SC, Schneeweiss S, Desai RJ. Cardiovascular Outcomes of Calcium-Free vs Calcium-Based Phosphate Binders in Patients 65 Years or Older With End-stage Renal Disease Requiring Hemodialysis. JAMA Intern Med. 2019;179(6):741-9.
  44. Jovanovich A. Time to Reconsider Calcium-Based Phosphate Binders in Dialysis? A Call for a Well-Designed Randomized Controlled Trial. Am J Kidney Dis. 2020;75(3):453-5.
  45. Almueilo SH. Quality of Life on Online Hemodiafiltration (HDF). Advances in Hemodiafiltration2016.

P/N 104622-01 Rev A 02/2021