PRESENTED BY
FRANCISCO MADUELL

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Francisco Maduell

Hemodiafiltration (HDF) has been introduced to practice as a dialysis modality in the late 1990s pertaining to the development of techniques for the on-line production of sterile infusate from the dialysate. This therapy combines conventional diffusive hemodialysis (HD) with the convectional component of hemofiltration, thus offering potential added benefits of improved larger molecule clearance in addition to good small molecule clearance. There have been no unfavorable studies published about this method during the 25 years of its utilization. However, even though significant improvements have been achieved with HDF and high-flux HD (HF-HD) in terms of prolonged survival and improved quality of life, long-term outcomes are still suboptimal and end-stage renal disease presents ever-growing costs to healthcare systems worldwide. Thus, there is still an unmet need for more efficient and less technically demanding dialysis techniques.

Recently, a new generation of HD membranes has emerged, providing substantial clearance of the so-called „middle molecules”, suspected to play a large part in the morbidity and mortality of dialysis patients (2). These medium cut-off (MCO) membranes allow the removal of middle molecules up to approximately 50kD, exceeding even the clearance range provided by HDF, but with significantly less albumin loss (2). The application of MCO membranes in a classic dialysis modality characterizes a new technique called expanded hemodialysis (HDx). This dialysis modality does not need specific software or dedicated hardware, making its application possible in every setting where the quality of dialysis fluid meets current standards (3). The pore size distribution combined with a unique internal architecture is the key feature determining the favorable sieving properties of the MCO membranes compared to the classic high-flux membranes. Thus, HDx has been promoted as a step closer to mimicking the function of the native kidney, and with less demanding technology (Figure 1). Whether this is truly the case is now a matter of debate.

Figure 1. The efficiency of different dialysis techniques in substance removal (4)

Is HDx superior to HF- HD and/or HDF?
The list of known clinical advantages of on-line HDF is long and includes better removal of uremic toxins, better control of anemia and mineral metabolism, improvement in fluid overload control, hemodynamic stability and inflammatory status, arterial endothelial function, and left ventricular function, resulting in reduced cardiovascular risk. The anticipated benefit of HDF on the overall survival of HD patients has been observed in several randomized controlled studies, as well as in national registries from France, Australia, and New Zealand (1). Unfortunately, its worldwide spread is limited by logistical, regulatory, and economic investments, since the technique requires an ultrapure water-loop, extra devices, and frequent upkeeping to maintain the quality of water delivered to the patient (5).

The first study comparing the results of HDx with MCO prototype dialyzers with HF and HDF dialyzes was published only three years ago (6). It concluded that MCO dialyzers remove a wide range of middle molecules more effectively than HF-HD, and even exceed the performance of high-volume HDF for large solutes, particularly lambda free light chains. However, even though albumin loss was moderate with MCO, it was greater than with HF-HD and HDF (6). One later study observed no significant difference between HDF and HDx in the removal of urea, creatinine, β2-microglobulin, myoglobin, and albumin (7). Nevertheless, another research showed superior efficiency of HDx in removing larger middle molecules, myoglobin, and prolactin, compared to HDF (8). Similar results were reported by García-Prieto et al, deducing that MCO HD is superior to standard HF-HD in the removal of middle and larger middle molecules and is not inferior to HDF in the clearance of small and larger middle molecules (9). Taken together, these studies reported somewhat conflicting results concerning the efficacy of HDx with MCO membranes in removing beta2-microglobulin, myoglobin, prolactin, and lambda free light chains.
A recently published study proposed a Global Removal Score (GRS) as a new useful tool for measuring dialyzer effectiveness calculated based on the removal rates of urea, beta2-microglobulin, myoglobin, prolactin, alpha1-microglobulin, and alpha1-acid glycoprotein, and albumin (10). The values of GRSs for the evaluated MCO and eight HDF dialyzers are shown in Figure 2. This study reported no significant differences in removal rates of neither of the examined substances with neither of the dialyzers. The dialysate albumin loss was acceptably below 3.5 g in all situations, without significant differences (10).

Figure 2. Global Removal Scores for one MCO and eight different HDF dialyzers (10)

What is the role of HDF prescription?
Compared to conventional HD, pre-dilution on-line HDF (pre-HDF), especially with high substitution volumes, is associated with improved overall survival, with a trend towards improved cardiovascular survival (11). However, at lower blood flow rates, post-dilution HDF (post-HDF) showed superiority in removing solutes over pre-HDF, as well as HDx, HF-HD, and HD (12). HDx was the closest alternative to post-HDF, and was superior to HD and pre-HDF (12). Albumin loss was highest in post-HDF, but still within an acceptable range. Another study, by Kim et al. presented somewhat different results, concluding that HDx significantly better removes large middle molecules and free light chains than pre-HDF and conventional HD, without the need for large convection volumes or high blood flow rates (13).

A very recently published study addressed the intriguing point of whether the amount of infusion flow may increase the efficiency of HDF to exceed the performance of HDx. The study confirmed the superiority of post-HDF over HDx at certain values of replacement volume, convective volume, ultrafiltration flow, and filtration fraction. The minimum convective volume, ultrafiltration flow, and filtration fraction in HDF from which it was possible to overcome the efficacy of HDx were 19.2l, 80.6ml/min, and 23% respectively at blood flow of 350ml/min, and 17.6 L, 74.1 mL/min and 18.6% respectively at blood flow of 400 mL/min (14). Finally, based on all these data, the presumed Global Removal Scores for selected treatment modalities are presented in Figure 3.

References

1. Maduell F, Moreso F, Pons M, et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients [published correction appears in J Am Soc Nephrol. 2014 May;25(5):1130]. J Am Soc Nephrol. 2013;24(3):487-497.

2. Wolley M, Jardine M, Hutchison CA. Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules. Clin J Am Soc Nephrol. 2018;13(5):805-814.

3. Ronco C, Marchionna N, Brendolan A, Neri M, Lorenzin A, Martínez Rueda AJ. Expanded haemodialysis: from operational mechanism to clinical results. Nephrol Dial Transplant. 2018;33(suppl_3):iii41-iii47.

4. Maduell F. HDF vs. Medium cut-off dialyzers. 57th European Renal Association – European Dialysis Transplantation Association (fully virtual), June 6, 2020. Available on the Virtual Meeting.

5. Florens N, Juillard L. Expanded haemodialysis: news from the field. Nephrol Dial Transplant. 2018;33(suppl_3):iii48-iii52.

6. Kirsch AH, Lyko R, Nilsson LG, et al. Performance of hemodialysis with novel medium cut-off dialyzers. Nephrol Dial Transplant. 2017;32(1):165-172.

7. Belmouaz M, Diolez J, Bauwens M, et al. Comparison of hemodialysis with medium cut-off dialyzer and on-line hemodiafiltration on the removal of small and middle-sized molecules
. Clin Nephrol. 2018;89(1):50-56.

8. Reque J, Pérez Alba A, Panizo N, Sánchez-Canel JJ, Pascual MJ, Pons Prades R. Is Expanded Hemodialysis an Option to Online Hemodiafiltration for Small- and Middle-Sized Molecules Clearance?. Blood Purif. 2019;47(1-3):126-131.

9. García-Prieto A, Vega A, Linares T, et al. Evaluation of the efficacy of a medium cut-off dialyser and comparison with other high-flux dialysers in conventional haemodialysis and online haemodiafiltration. Clin Kidney J. 2018;11(5):742-746.

10. Maduell F, Rodas L, Broseta JJ, et al. Medium Cut-Off Dialyzer versus Eight Hemodiafiltration Dialyzers: Comparison Using a Global Removal Score. Blood Purif. 2019;48(2):167-174.

11. Kikuchi K, Hamano T, Wada A, Nakai S, Masakane I. Predilution online hemodiafiltration is associated with improved survival compared with hemodialysis. Kidney Int. 2019;95(4):929-938.

12. Maduell F, Broseta JJ, Rodas L, et al. Comparison of Solute Removal Properties Between High-Efficient Dialysis Modalities in Low Blood Flow Rate. Ther Apher Dial. 2020;24(4):387-392.

13. Kim TH, Kim SH, Kim TY, et al. Removal of large middle molecules via haemodialysis with medium cut-off membranes at lower blood flow rates: an observational prospective study. BMC Nephrol. 2019;21(1):2.

14. Maduell F, Broseta JJ, Gómez M, et al. Determining factors for hemodiafiltration to equal or exceed the performance of expanded hemodialysis [published online ahead of print, 2020 Apr 12]. Artif Organs. 2020;10.1111/aor.13700.

More readings suggested by the lecturer

1. Ronco C, La Manna G. Expanded Hemodialysis: A New Therapy for a New Class of Membranes. Contrib Nephrol. 2017;190:124-133.

2. Maduell F. Hemodiafiltration versus conventional hemodialysis: Should “conventional” be redefined? Semin Dial. 2018;31(6):625-632.

3. Maduell F, Rodas L, Broseta JJ, et al. High-permeability alternatives to current dialyzers performing both high-flux hemodialysis and postdilution online hemodiafiltration. Artif Organs. 2019;43(10):1014-1021.

4. Ronco C. The Rise of Expanded Hemodialysis. Blood Purif. 2017;44(2):I-VIII.

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