In the last decades, renal replacement therapy with hemodialysis has become a standard of care for patients with ESRD. Despite continuous improvement, annual mortality among these patients ranges between 15% and 25%.1 , 2 3 4 post hoc analysis in diabetic patients, showed that high-flux hemodialysis improved long-term survival in patients with hypoalbuminemia.
Clearance of middle-to-large molecules can be increased by combining diffusive and convective transport through hemodiafiltration. The introduction of online hemodiafiltration (OL-HDF) using ultrapure dialysate as the source of the replacement fluid has allowed the convective volume to be increased and has reduced the cost of the procedure.5 6 – 11 12 13 – 15 16 , 17
In 2007, the Catalonian Health Authorities approved a specific additional reimbursement for OL-HDF to dialysis care providers and the Catalonian Society of Nephrology promoted this randomized study (On-Line Hemodiafiltration Survival Study, or Estudio de Supervivencia de Hemodiafiltración On-Line [ESHOL]) to compare the effect of OL-HDF over hemodialysis on patient survival.18
Results
Baseline Patient Characteristics
During the recruitment period, 939 patients were assessed for eligibility in 27 Catalonian dialysis units. Thirty-three patients were not included in the randomization, 18 because they did not meet the inclusion criteria, 5 because they refused to provide informed consent, and 10 for other reasons. Finally, 906 patients were included in the randomization (Figure 1 ). Patient characteristics at enrollment in both groups are summarized in Table 1 .
Figure 1: Flow chart of study populations, including the number of patients who were screened, underwent randomization, and completed the study treatment or presented the primary variable. HD, hemodialysis.
Table 1: Demography characteristics and baseline parameters in randomized patients
Hemodialysis Treatment
Hemodialysis treatment parameters during follow-up are summarized in Table 2 . Length of dialysis time did not differ between the two groups, whereas blood flow (Qb) and dialysate flow (Qd) were higher in the OL-HDF group throughout the study. Among patients randomized to hemodialysis, approximately 92% (range, 91.8%–93.6%) were treated with high-flux membranes during the study. The median quarterly replacement volume and convective volume during the study in the OL-HDF group ranged from 20.8 to 21.8 L/session and 22.9–23.9 L/session, respectively.
Table 2: Dialysis parameters outcome
Primary Outcome
All-Cause Mortality
The mean follow-up was 1.91±1.10 years (median 2.08 years; interquartile range [IQR], 0.86–3.00). During the observation period, 355 patients prematurely finished the study (Figure 1 ) because of kidney transplantation (n =180), change of dialysis unit (n =58), organizational changes (n =33), withdrawal of consent (n =27), need for a temporary catheter (n =19), change of treatment (n =15), or because of other, not predefined reasons (n =23). All of these patients were censored at the time of premature termination.
There were 207 deaths (22.8%) during the follow-up, with 3-year all-cause mortality rates of 18.6% and 27.1% in the OL-HDF and the hemodialysis groups, respectively, implying a 30% risk reduction (hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.53–0.92; P =0.01) (Figure 2 and Table 3 ). The main causes of death were cardiovascular diseases (44.4%) and infectious diseases (15.5%).
Figure 2: Kaplan–Meier curves for 36-month survival in the intention-to-treat population (P =0.01 by the log-rank test). HD, hemodialysis.
Table 3: Primary outcome: Mortality
Sensitivity analyses were performed on the basis of the following variables, which were found to be independent predictors for all-cause mortality: age, sex, diabetes, the Charlson comorbidity index, and vascular access (Table 4 ). First, these variables were included in four distinct multivariate analyses to assess the covariate-adjusted risk estimates for the intervention. Second, the treatment risk estimates were also calculated in all subgroups arising from these variables, using the original categories for nominal variables and tertiles for continuous variables. All HRs were consistent for both types of analysis and the statistical tests for interaction were not significant except for the Charlson comorbidity index (Figure 3 ).The estimated number needed to treat (NNT) for all-cause mortality at 1, 2, and 3 years was 9.75 (5.03–47.41), 7.67 (4.32–33.57), and 7.67 (4.51–31.83), respectively (Table 3 ).
Table 4: Univariate cox regression analysis for all-cause mortality
Figure 3: Sensitivity analyses for the main outcome showing HRs (95% CIs) for the intervention based on relevant variables that were found to be independent predictors for all-cause mortality. Multivariate I, age, sex, vascular access, diabetes, and the Charlson comorbidity index (excluding diabetes); multivariate II, age, sex, vascular access, and the Charlson comorbidity index (excluding diabetes); multivariate III, age, sex, vascular access, and diabetes; multivariate IV, age, sex, vascular access, and the Charlson comorbidity index (including diabetes); Y, yes; N, no; Cath, catheter; Fist, fistula; M, male; F, female; T1, T2, and T3, first, second, and third tertiles; HD, hemodialysis.
Secondary Outcomes
Cardiovascular Mortality
The analysis of the distinct causes of cardiovascular mortality (Table 3 ) showed no significant differences between groups in the number of deaths due to heart failure, ischemic heart disease, mesenteric thrombosis, arrhythmia, or peripheral arteriopathy. However, stroke mortality was significantly lower in the OL-HDF group than in the hemodialysis group (P =0.03 by the log-rank test). The Cox proportional hazards model showed that OL-HDF caused a significant 61% risk reduction in mortality from stroke (HR, 0.39; 95% CI, 0.16–0.93).
Other Causes of Mortality
Infection-related mortality was also significantly lower in the OL-HDF group than in the hemodialysis group (P =0.03 by the log-rank test; Table 3 ). The Cox proportional hazards model showed that OL-HDF produced a significant 55% risk reduction in mortality from infection (HR, 0.45; 95% CI, 0.21–0.96). There were no differences in sudden death, cancer, cachexia, or other causes of mortality (Table 3 ).
Hospitalizations
The rate of all-cause hospital admissions showed a relative risk reduction of 22% favorable to the OL-HDF group (rate ratio, 0.78; 95% CI, 0.67–0.90; P =0.001) (Table 5 ).
Table 5: Outcome data: Hospitalizations and intradialysis symptoms
BP and Intradialysis Tolerance
Neither predialysis nor postdialysis systolic and diastolic BP were significantly modified by treatment, although BP control was improved in both treatment groups during the study (Supplemental Table 1). The percentage of patients requiring antihypertensive drugs did not differ between the groups (Supplemental Table 2).
The incidence of intradialysis symptoms was affected by treatment assignment. There were 679.2 intradialysis hypotension episodes per 100 patient-years in the OL-HDF group versus 937.7 episodes per 100 patient-years in the hemodialysis group (rate ratio, 0.72; 95% CI, 0.68–0.77; P <0.001) (Table 4 ). The number of intradialysis episodes of arrhythmia and thoracic pain episodes did not differ between the groups (Table 5 ).
Dialysis Dose and β 2 -Microglobulin
During the study period, the dialysis dose significantly increased in both groups but was higher in patients randomized to OL-HDF than in those randomized to hemodialysis (Supplemental Table 1).
OL-HDF led to a lower accumulation of β 2 -microglobulin than did hemodialysis. β 2 -Microglobulin increased from month 0 to month 36 in both groups but to a lesser extent in the OL-HDF group (Supplemental Table 1).
Nutrition
Dry body weight and albumin changes during follow-up did not differ between treatment groups. However, albumin significantly decreased in both groups throughout the study. The normalized protein catabolic rate was higher in patients randomized to OL-HDF (Supplemental Table 1).
Anemia
Hemoglobin, the transferrin saturation index, and ferritin did not differ between the groups during the study period (Supplemental Table 1). Moreover, there were no differences in the proportion of patients treated with distinct ESA. Intravenous iron supplements and ESA doses did not differ between the groups (Supplemental Table 2).
Phosphate and Other Biochemical Parameters
Serum phosphate (Supplemental Table 1) and the number of phosphate binding tablets (Supplemental Table 2) did not significantly change during the study and did not differ between the treatment groups. There were no significant changes for predialysis C-reactive protein, creatinine, sodium, potassium, uric acid, calcium, and intact parathyroid hormone (Supplemental Table 3).
Influence of Convection Volume on All-Cause Mortality
In post hoc analyses, the association between convective volume per session in comparison with convective volume per square meter of body surface area and convective volume per body mass index was evaluated (Supplemental Table 4). The convective volume per session is the variable that best represents the trend compared with the ratio of the convective volume per session both with the body mass index and with the body surface area. In the group of patients with the highest delivered convection volume, mortality in the intermediate tertile (23.1–25.4 L) and upper tertile (>25.4 L) was considered lower than that in patients randomized to hemodialysis (HR, 0.60; 95% CI, 0.39–0.90; and HR, 0.55; 95% CI, 0.34–0.84, respectively).
Discussion
In this prospective, randomized clinical trial, we found that high-efficiency OL-HDF in patients with ESRD on hemodialysis was associated with a 30% reduction in all-cause mortality compared with conventional high-flux hemodialysis. This mortality reduction was related to a significant risk reduction for stroke and infectious mortality. The estimated NNT showed that to prevent one annual death, eight patients would need to be switched from hemodialysis to OL-HDF. To our knowledge, this is the first prospective, randomized clinical trial showing that high-efficiency postdilution OL-HDF reduces all-cause mortality compared with conventional hemodialysis in the chronic prevalent population. The survival benefit observed in this study has sufficient statistical robustness to support the finding that OL-HDF was the major determinant of survival. Furthermore, the results were consistent in distinct subgroups of patients according to age, sex, diabetes mellitus, the Charlson comorbidity index, and vascular access. Although all patient groups benefitted from OL-HDF, the subgroups obtaining the greatest benefit were older, had no diabetes, were dialyzed through an arteriovenous fistula, and had a higher Charlson comorbidity index.
The ESHOL study was designed to compare high-flux hemodialysis versus postdilution OL-HDF. However, a small proportion of patients on low-flux hemodialysis (6%) were allowed to be included; therefore, this study represents routine clinical practice in Catalonia. In this study, we did not record the number of screened patients, which is a potential limitation to the external validity of the study. However, the patients included in this trial corresponded to >25% of all patients maintained on hemodialysis in Catalonia and the mean age as well as the proportion of patients with diabetes were similar to data reported by the Catalonian Registry of Renal Patients.1 3 4 16
There is some controversy on the potential benefits of OL-HDF in mortality risk reduction. Retrospective, observational studies suggested that OL-HDF could improve patient survival,12 – 15 16 , 17 16 17 post hoc analysis, both studies showed a 39% and 46% mortality risk reduction in patients receiving high convection volumes (>22 and >20 L/session, respectively). Similarly, the post hoc analysis in the ESHOL study showed a 40% and 45% mortality risk reduction in patients receiving convection volumes between 23–25 L/session and >25 L/session, respectively. These results provide evidence of the need to deliver high convection volumes to reduce all-cause mortality. To achieve this goal, high blood flow rates and long dialysis times are required. In this ESHOL study, the mean blood flow rate was higher (387 ml/min) than in the CONTRAST and Turkish studies (300 and 310 ml/min, respectively), whereas the mean length of dialysis was longer (236 minutes) than in the CONTRAST study (226 minutes) and was similar to that of the Turkish study (236 minutes). These factors led to a higher mean delivered convection volume in this study (23.7 L/session) than in the CONTRAST (20.7 L) and Turkish (20.7 L) studies. These results indicate that the treatment modality could modify patient survival when a sufficient convective volume is reached. Therefore, in future studies, the convective volume dose should be defined as a minimum postdilution volume, a minimum infusion flux, a convective volume normalized to body-size, or other factors.
The reduction in all-cause mortality associated with OL-HDF treatment observed in this trial was focused on cardiovascular and infectious diseases. Cardiovascular disease is the most common cause of mortality in chronic hemodialysis patients and the mortality rate is still 10 times higher than in the general population.19 20 21 22 23 , 24 11 25 26
Clearance of middle-to-large molecules depends on the type of dialysis membrane and the amount of convection volume and may be increased with OL-HDF treatment. However, the observed increase of β 2 -microglobulin serum levels in both groups during this study was an unexpected finding. Previous data27 β 2 -microglobulin reduction ratio but this does not mean that predialysis levels were reduced, because β 2 -microglobulin has a low distribution volume.28 β 2 -microglobulin levels were reduced after patients were switched from high-flux hemodialysis to OL-HDF.7 , 29 β 2-microglobulin serum levels, was not monitored during the study period. These results suggest that the benefit of OL-HDF to patient survival partly depends on clearance of molecules other than β 2 -microglobulin. OL-HDF can remove other middle-sized molecules or protein-bound uremic toxins more efficiently than hemodialysis, which may influence endothelial function, inflammatory status, or vascular calcification, providing cardioprotective effects and/or improving the immunologic system.
The ESHOL study has some weaknesses but also major strengths. A limitation is that a small proportion of patients (6.3%) were treated with low-flux membranes and, additionally, residual renal function was not monitored. Small differences might be suggested in diabetic patients, grafts, or catheters between the two groups in our study. To address this point, additional multivariate Cox regression sensitivity analyses were conducted, adjusting by age, sex, diabetes, the Charlson comorbidity index, and type of vascular access. The results from the multivariate analyses were robust and the risk estimates and 95% CIs were very much in line with the main analysis conducted with any baseline adjustments. Because this was a randomized study, the apparent small baseline differences were considered likely to be obtained by chance rather than due to bias, and this statement holds true because of the randomization procedure. The lower number of intradialysis hypotension episodes observed in this study was not apparently due to major differences in sodium removal among treatments, as suggested by the similar pretreatment and post-treatment plasma sodium concentrations, the similar ultrafiltration rate, and the similar dry body weight behavior during the follow-up; however, our measurement was a crude estimation of dialytic sodium removal and therefore the possibility of a negative sodium balance during OL-HDF could not be ruled out.23
In summary, the results of the ESHOL trial indicate that high-efficiency postdilution OL-HDF reduces all-cause mortality versus conventional hemodialysis in prevalent patients. Furthermore, the main causes of mortality, cardiovascular and infectious diseases, were significantly reduced by OL-HDF. In view of these results, OL-HDF may become the first-line option in hemodialysis patients.
Concise Methods
Study Design
The study design was previously reported.30 18
The primary objective was to assess the effect of postdilution OL-HDF compared with hemodialysis, either low-flux or high-flux, on all-cause mortality. The primary outcome variable was the time to occurrence of death from any cause. Key secondary outcomes were cardiovascular mortality, other causes of mortality, all-cause hospitalization, dialysis dose (Kt/V and urea reduction ratio), BP control and intradialysis tolerance (symptomatic hypotension episodes, arrhythmia, and thoracic pain), nutrition (dry body weight, normalized protein catabolic rate, albumin), anemia, and phosphate and β 2 -microglobulin serum levels.
Study Population
The study population was previously described.30
Randomization and Dialysis Treatment Parameters
Patients were randomized 1:1 to continue on thrice-weekly hemodialysis or to start OL-HDF three times a week. A central computerized random-generator was utilized to allocate patients to each study group and randomization was stratified by center. The length of the recruitment period was 16 months and the study was completed in order to provide a follow-up of 3 years for all surviving patients.
Treatment Procedures
Synthetic high-flux dialyzers were used for OL-HDF (FX60: 59.7% and FX80: 8.6% [Fresenius Medical Care, Bad Homburg, Germany]; Polyflux 170H: 7.9%, Polyflux 210H: 10.3%, and Arylane H9: 1.5% [Gambro AB, Stockholm, Sweden]; or other dialyzers: 12.5%). Patients randomized to hemodialysis were treated with synthetic high-flux (FX60: 58.7%, FX80: 8.4%, Polyflux 170H: 10.4%, Polyflux 210H: 5.5%, Arylane H9: 0.9% and other dialyzers: 12.5%) or low-flux dialyzers (8.1%).
Both OL-HDF and hemodialysis were performed with ultrapure dialysis fluids, defined as <0.1 CFU/ml and <0.03 EU/ml. The length of dialysis sessions in each treatment modality was not modified.
When OL-HDF could not be performed temporarily for technical reasons, affected patients were treated with the same high-flux membranes. For patients on postdilution OL-HDF, a minimum of 18 L/session of replacement volume was requested. Patients not receiving the allocated treatment modality for >2 consecutive months were withdrawn from the study.
The composition of dialysate was the same in both groups, as was the reinfusate in OL-HDF (sodium 138–140 mmol/L, potassium 1.5–2.0 mmol/L, calcium 1.25–1.75 mmol/L, magnesium 0.5 mmol/L, chloride 106–109 mmol/L, bicarbonate 34–37 mmol/L, acetate 3–4 mmol/L, and glucose 1.0 g/L).
Study Variables
Before randomization, the Charlson comorbidity index score was calculated for each patient. The following parameters were recorded at baseline and every 3 months: dialyzer characteristics, dialysis time, Qb, Qd, vascular access, replacement volume, dry body weight, predialysis and postdialysis body weight, convective volume, and predialysis and postdialysis systolic and diastolic BP.
The following laboratory data were recorded at baseline and every 3 months: predialysis urea, creatinine, bicarbonate, sodium, potassium, C-reactive protein, uric acid, albumin, calcium, phosphate, intact parathyroid hormone, β 2 -microglobulin, hemoglobin, transferrin saturation index, and ferritin. Using predialysis and postdialysis BUN in a mid-week dialysis session, the urea reduction rate, dialysis dose (Kt/V by Daugirdas’ second-generation single-pool variable volume formula) and normalized protein catabolic rate were calculated by standard formulas. All laboratory determinations were performed locally by standard procedures in certified laboratories. The doses of ESAs, iron supplements, antihypertensive drugs, and phosphate binders were also recorded at baseline and every 3 months.
Clinical monitoring included intradialysis symptoms (symptomatic hypotension, episodes of arrhythmia and thoracic pain), hospital admissions for any reasons, and withdrawals from the study and their causes. To calculate the number of dialysis sessions complicated by intradialysis symptoms, the last 12 sessions preceding the quarterly visit were considered.
Sample Size
According to the Catalonian Registry of Renal Patients, 3-year patient survival in hemodialysis patients was 70%.1 12
Statistical Analyses
All data analyses were carried out according to a pre-established statistical analysis plan. All-cause mortality, as well as cardiovascular death, cachexia, infection, tumors, sudden death, and death from other causes were described by means of the Kaplan–Meier method. The log-rank test was used for hypothesis testing, and the HR and its 95% CI were estimated from the unadjusted Cox model. Additional multivariate Cox regression sensitivity analyses were conducted, adjusting by age, sex, diabetes, the Charlson comorbidity index (the original scale and also excluding diabetes), and the type of vascular access to assess the robustness of the study results. The NNT estimated after the switch from hemodialysis to OL-HDF was also calculated.
Time repeated measurements were analyzed using linear mixed models including treatment, time, and the treatment by time interaction term. Gaussian continuous variables were approached through mixed models for repeated measurements, adjusting by the baseline value and, for non-Gaussian data (binomial and Poisson distribution variables), by penalized quasi-likelihood under restricted maximum likelihood models. Treatment inferences, effect estimates, and 95% CIs were taken from these models.
Two-sided significance tests were used throughout, and a P value of <0.05 was considered significant. All statistical analyses were performed using the SAS 9.2 statistical package.
Disclosures
None.
The following institutions and investigators participated in the ESHOL study: M. Pons, B. Insensé, C. Perez, and T. Feliz (CETIRSA, Barcelona); R. Ramos, M. Barbetta, and C. Soto (Hospital San Antonio Abad, Vilanova i la Geltru); J. Mora, A. Juan, and O. Ibrik (Fresenius Medical Care, Granollers); A. Foraster and J. Carreras (Diaverum Baix Llobregat, Hospitalet); F. Moreso, J. Nin, and A. Fernández (Fresenius Medical Care, Hospitalet); J. Soler, M. Arruche, C. Sánchez, and J. Vidiella (Fresenius Medical Care, Reus); F. Barbosa, M. Chiné, and S. Hurtado (Fresenius Medical Care Diagonal, Barcelona); J. Llibre, A. Ruiz, M. Serra, M. Salvó, and T. Poyuelo (CETIRSA, Terrassa); F. Maduell, M. Carrera, N. Fontseré, M. Arias, and Josep M. Campistol (Hospital Clínic, Barcelona); A. Merín and L. Ribera (Fresenius Medical Care Julio Verne, Barcelona); J.M. Galceran, J. Mòdol, E. Moliner, and A. Ramirez (Fundació Althaia, Manresa); J. Aguilera and M. Alvarez (Hospital Santa Tecla, Tarragona); B. de la Torre and M. Molera (Diaverum Bonanova, Barcelona); J. Casellas and G. Martín (Diaverum IHB, Barcelona); E. Andres and E. Coll (Fundació Puigvert, Barcelona); M. Valles and C. Martínez (Hospital Josep Trueta, Girona); E. Castellote (Hospital General, Vic); J.M. Casals, J. Gabàs, and M. Romero (Diaverum, Mataró); A. Martinez-Castelao and X. Fulladosa (Hospital Universitari Bellvitge, Hospitalet); M. Ramirez-Arellano and M. Fulquet (Hospital de Terrassa); A. Pelegrí, M. el Manouari, and N. Ramos (Diaverum Verge de Montserrat, Santa Coloma); J. Bartolomé (Centre Secretari Coloma, Barcelona); R. Sans (Hospital de Figueres); E. Fernández and F. Sarró (Hospital Arnau de Vilanova, Lleida); T. Compte (Hospital Santa Creu, Tortosa); F. Marco and R. Mauri (Diaverum Nephros, Barcelona); and J. Bronsoms (Clínica Girona). The clinical trials unit comprised J.A. Arnaiz, H. Beleta, and A. Pejenaute (UASP Farmacología Clínica, Hospital Clínic Barcelona). Statistical analyses were performed by F. Torres, J. Ríos, and J. Lara (Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona; and Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona).
The Catalan Society of Nephrology has endorsed the ESHOL study. This study was partly supported by grants from Fresenius Medical Care and Gambro through the Catalan Society of Nephrology.
Published online ahead of print. Publication date available at www.jasn.org
See related editorial, “Has the Time Now Come to More Widely Accept Hemodiafiltration in the United States?,” on pages 332–334.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2012080875/-/DCSupplemental
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