Several cohort studies addressing hard clinical end points also identified that HDF may improve patient survival (1-3). The main findings of these studies are summarized in the table. In this section, the most recent and significant outcomes were selected.

Reference	Study design	Renal Replacement Modalities	Number of patients	Effect/primary end point
Canaud et al. (DOPPS) 4	Prospective observational	LF/HF-HD ⬌ olHDFpost	2165	Improved survival in HDF (35%)
Jirka et al. 2	Retrospective observational	HF-HD ⬌ olHDFpost	2564	Improved survival in HDF (37%)
Bosch et al. 3	Retrospective observational	HF-HD ⬌ Double high-flux HDF	183	Improved survival in HDF (60%) compared with USRDS outcomes
Panichi et al. (RISCAVID) 6	Prospective observational	HF-HD ⬌HDFpost	757	Improved survival in HDF (22%)
Vilar et al. 1	Retrospective observational	HF-HD ⬌HDFpost	858	Improved survival in HDF (34%)

HF High-Flux; LF Low-Flux; HD hemodialysis; HDF hemodiafiltration: ol-HDF online hemodiafiltration; USRDS United States Renal Data System

 

The prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) suggested first that patients treated with relatively high substitution volume HDF (15–25 L/session) had a 35% lower mortality than those treated with low-flux HD (4). However, this landmark finding could not be confirmed in a more recent analysis of DOPPS with a new dataset(5).

The ‘RISchio CArdiovascolare nei pazienti afferenti all’ Area Vasta In Dialisi’ (RISCAVID) study is a prospective multicenter registry study aimed at exploring risk factors in HD patients and the impact of different HD modalities (6). A total of 757 HD patients were prospectively followed for up to 30 months to assess all-cause and cardiovascular (CV) mortality. Nutritional markers, anemia management and sensitive inflammatory biomarkers were monitored. Patients were stratified into three groups according to RRT modality: standard bicarbonate HD (BHD) (n = 424), low volume hemodiafiltration (bag HDF) (n = 204) and online HDF (n = 129), with a mean of 14 L and 23 L infusion volume per session, respectively. Cox proportional hazards regression and multivariate analyses were performed to assess their relative risk of death. All-cause and CV mortality was 12.9%/year and 5.9%/year, respectively. Patients with combined high levels of CRP and pro-inflammatory cytokines showed an increased risk for CV (RR 1.9) and all-cause mortality (RR 2.57). Multivariate analysis adjusted for comorbidities and demographics showed that high CRP and IL-6 were associated with worst outcomes, while HDF was associated with significant cumulative benefits on patient survival (6). 

More recently three large national cohort studies (French Registry, REIN (7); Australia-New-Zealand Registry, ANZ (8); Japan Registry, JSDT (9) reflecting real-life practices and no selection biases were reported. A summary is presented in the table. 

 

Data Registry	Renal Replacement Modalities	Number of patients	Effect/primary end point
French National Data Registry (REIN) 7	HF-HD ⬌ olHDFpost	28407	Improved survival in HDF All-Cause Mortality 23% CV Mortality 34%
Australia New-Zealand Dialysis and Transplant Registry 8	HF-HD ⬌ olHDFpost	26961	Improved survival in HDF All-Cause Mortality 21% Australia, 12% New-Zeeland CV Mortality 22% Australia only
Japanese Society for Dialysis Therapy National Data Registry 9	HF-HD ⬌ olHDFpre	10000	Improved survival in HDF All-Cause Mortality 17%

HF High-Flux; LF Low-Flux; HD hemodialysis; HDF hemodiafiltration: ol-HDF online hemodiafiltration; HDFpost postdilution HDF; HDFpre predilution HDF;  CV cardiovascular

 

The first study using data from the French National Renal Epidemiology and Information Network (REIN) registry assessed the effects of online HDF on mortality in the total population of patients beginning dialysis in France between January 1, 2008 and December 31, 2011 (7). Analyses were performed at both patient and facility levels. Out of a total of 28,407 patients, 5526 received HDF for a median of 1.21 years, with 2254 receiving only HDF. Irrespective of analysis at a patient or a facility level, HDF was associated with lower all-cause and cardiovascular mortality than HD, with the beneficial effect more pronounced in those patients treated exclusively with HDF. 

The second study using data from the Australia and New Zealand Dialysis and Transplant Registry, all adult patients who commenced HD in Australia and New Zealand between 2000 and 2014 (8). The primary outcome was all-cause mortality. Cardiovascular mortality was the secondary outcome. Outcomes were measured from the first hemodialysis treatment and were examined using multivariable Cox regression analyses. Patients were censored at permanent discontinuation of hemodialysis or at 31 December 2014. The study included 26.961 patients (4110 HDF, 22.851 HD; 22.774 Australia, 4187 New Zealand) with a median follow-up of 5.31 years. Compared with standard HD, HDF was associated with a significantly lower risk of all-cause mortality (HR Australia 0.79; HR New Zealand 0.88). There was also an association between HDF and reduced cardiovascular mortality (HR 0.78). HDF was associated with superior survival across patient subgroups of age, sex, and comorbidity in both countries.

Finally, the third study comes from the Japanese Society for Dialysis Therapy Renal Data Registry, using a propensity-matched cohort of 5,000 pairs of patients treated with conventional high-flux HD or predilution HDF; one-year follow-up was performed (9). All-cause and cardiovascular mortality were compared between the two groups. HDF was associated with improved overall survival compared to HD (HR all cause-mortality 0.83), with a trend towards improved cardiovascular survival. Among patients treated with predilution on-line hemodiafiltration, those treated with high substitution volumes (≥40.0 L/ses) had improved all-cause and cardiovascular survival compared to those treated with low substitution volumes (<40.0 L/ses) or those on hemodialysis. The optimal predilution substitution volume associated with improved overall survival was estimated to be 50.5 L/session. This observational study suggests that HDF, especially with high substitution volumes, is associated with a reduction in all-cause and cardiovascular mortality.

In brief, these large registry studies reflecting current clinical practices and adjusted for main confounding factors have shown that patients receiving HDF had significant improved survival expectancy (up to 30%) as compared to high flux hemodialysis paired groups. Furthermore, patient survival benefits relied mostly on a reduced cardiac mortality and were associated with the convective dose delivered. 

1. Vilar E, Fry AC, Wellsted D, Tattersall JE, Greenwood RN, Farrington K. Long-term outcomes in online hemodiafiltration and high-flux hemodialysis: a comparative analysis. Clin J Am Soc Nephrol. 2009;4(12):1944-53.
2. Jirka T, Cesare S, Di Benedetto A, Perera Chang M, Ponce P, Richards N, et al. Mortality risk for patients receiving hemodiafiltration versus hemodialysis. Kidney Int. 2006;70(8):1524; author reply -5.
3. Bosch JP, Lew SQ, Barlee V, Mishkin GJ, von Albertini B. Clinical use of high-efficiency hemodialysis treatments: long-term assessment. Hemodial Int. 2006;10(1):73-81.
4. Canaud B, Bragg-Gresham JL, Marshall MR, Desmeules S, Gillespie BW, Depner T, et al. Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS. Kidney Int. 2006;69(11):2087-93.
5. Locatelli F, Karaboyas A, Pisoni RL, Robinson BM, Fort J, Vanholder R, et al. Mortality risk in patients on hemodiafiltration versus hemodialysis: a ‘real-world’ comparison from the DOPPS. Nephrol Dial Transplant. 2018;33(4):683-9.
6. 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.
7. Mercadal L, Franck JE, Metzger M, Urena Torres P, de Cornelissen F, Edet S, et al. Hemodiafiltration Versus Hemodialysis and Survival in Patients With ESRD: The French Renal Epidemiology and Information Network (REIN) Registry. Am J Kidney Dis. 2016;68(2):247-55.
8. See EJ, Hedley J, Agar JWM, Hawley CM, Johnson DW, Kelly PJ, et al. Patient survival on haemodiafiltration and haemodialysis: a cohort study using the Australia and New Zealand Dialysis and Transplant Registry. Nephrol Dial Transplant. 2019;34(2):326-38.
9. 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):929-38.

      P/N 104622-01 Rev A 02/2021